Ensuring the patency of repaired vessels is pivotal in improving the success rate of digit replantation. There is no consensus on how to best approach postoperative treatment for digit replantation. The influence of postoperative treatment on the risk of failure of revascularization or replantation remains unclear. (1) Is there an increased risk of postoperative infection with early discontinuation of antibiotic prophylaxis? (2) How are anxiety and depression affected by a treatment protocol consisting of prolonged antibiotic prophylaxis and administration of antithrombotic and antispasmodic drugs and by the failure of a revascularization or replantation procedure? (3) Are there differences in the risk of revascularization or replantation failure based on the number of anastomosed arteries and veins? (4) What factors are associated with failure of revascularization or replantation? This retrospective study was conducted between July 1, 2018, and March 31, 2022. Initially, 1045 patients were identified. One hundred two patients chose revision of amputation. In all, 556 were excluded because of contraindications. We included all patients in whom the anatomic structures of the amputated part of the digit were well preserved, and those with an ischemia time for the amputated part that did not exceed 6 hours. Patients in good health without any other serious associated injuries or systemic diseases and those without a history of smoking were eligible for inclusion. The patients underwent procedures that were performed or supervised by one of four study surgeons. Patients were treated with antibiotic prophylaxis (1 week); patients treated with antithrombotic and antispasmodic drugs were categorized into the prolonged antibiotic prophylaxis group. The remaining patients treated with antibiotic prophylaxis for less than 48 hours and no antithrombotic and no antispasmodic drugs were categorized into the nonprolonged antibiotic prophylaxis group. Postoperative follow-up was for a minimum of 1 month. Based on the inclusion criteria, 387 participants with 465 digits were selected for an analysis of postoperative infection. Twenty-five participants with a postoperative infection (six digits) and other complications (19 digits) were excluded from the next stage of the study, in which we assessed factors associated with the risk of failure of revascularization or replantation. A total of 362 participants with 440 digits were examined, including the postoperative survival rate, variation in Hospital Anxiety and Depression Scale scores, the association between the survival rate and Hospital Anxiety and Depression Scale scores, and the survival rate based on the number of anastomosed vessels. Postoperative infection was defined as swelling, erythema, pain, purulent discharge, or a positive bacterial culture result. Patients were followed for 1 month. The differences in anxiety and depression scores between the two treatment groups and the differences in anxiety and depression scores based on failure of revascularization or replantation were determined. The difference in the risk of revascularization or replantation failure based on the number of anastomosed arteries and veins was assessed. Except for statistically significant variables (injury type and procedure), we thought that the number of arteries, number of veins, Tamai level, treatment protocol, and surgeons would be important. A multivariable logistic regression analysis was used to perform an adjusted analysis of risk factors such as postoperative protocol, injury type, procedure, number of arteries, number of veins, Tamai level, and surgeon. Postoperative infection did not appear to increase without prolonged use of antibiotic prophylaxis beyond 48 hours (1% 3 of 327 versus 2% 3 of 138; OR 2.4 95% confidence interval (CI) 0.5 to 12.0; p = 0.37). Intervention with antithrombotic and antispasmodic therapy increased the Hospital Anxiety and Depression Scale scores for anxiety (11.2 ± 3.0 versus 6.7 ± 2.9, mean difference 4.5 95% CI 4.0 to 5.2; p < 0.01) and depression (7.9 ± 3.2 versus 5.2 ± 2.7, mean difference 2.7 95% CI 2.1 to 3.4; p < 0.01). In the analysis based on the failure of revascularization or replantation, the Hospital Anxiety and Depression Scale scores for anxiety (11.4 ± 4.4 versus 9.7 ± 3.5, mean difference 1.7 95% CI 0.6 to 2.8; p < 0.01) and depression (8.5 ± 4.6 versus 7.0 ± 3.1, mean difference 1.5 95% CI 0.5 to 2.5; p < 0.01) were higher in the failed revascularization or replantation group than in the successful revascularization or replantation group. There was no increase in the artery-related risk of failure (one versus two anastomosed arteries: 91% versus 89%, OR 1.3 95% CI 0.6 to 2.6; p = 0.53). For patients with anastomosed veins, a similar outcome was observed for the two vein-related risk of failure (two versus one anastomosed vein: 90% versus 89%, OR 1.0 95% CI 0.2 to 3.8; p = 0.95) and three vein-related risk of failure (three versus one vein anastomosed: 96% versus 89%, OR 0.4 95% CI 0.1 to 2.4; p = 0.29). Factors associated with failure of revascularization or replantation included the mechanism of injury (crush: OR 4.2 95% CI 1.6 to 11.2; p < 0.01, avulsion: OR 10.2 95% CI 3.4 to 30.7; p < 0.01). Revascularization had a lower risk of failure than replantation (OR 0.4 95% CI 0.2 to 1.0; p = 0.04). Treatment with a protocol of prolonged antibiotics, antithrombotics, and antispasmodics was not associated with a lower risk of failure (OR 1.2 95% CI 0.6 to 2.3; p = 0.63). With proper wound debridement and patency of repaired vessels, prolonged use of antibiotic prophylaxis and regular antithrombotic and antispasmodic treatment may not be necessary for successful digit replantation. However, it may be associated with higher Hospital Anxiety and Depression Scale scores. Postoperative mental status is associated with digit survival. Well-repaired vessels, instead of the number of anastomosed vessels, could be critical to survival and decrease the influence of risk factors. Further research on consensus guidelines that compare postoperative treatment and the surgeon's level of expertise after digit replantation should be conducted at multiple institutions. Level III, therapeutic study.