Abstract Background It was hypothesized that splenectomy following trauma results in hypercoagulability. Methods A prospective, nonrandomized, single-center study was performed to evaluate coagulation parameters in trauma patients with splenic injury. Results Patients with splenectomy (n = 30) and nonoperative management (n = 50) were enrolled. Splenectomy patients were older, had higher Injury Severity Scores, and had longer intensive care unit and hospital stays ( P < .05). Splenectomy patients had significantly increased white blood cell counts and platelet counts at baseline and follow-up ( P < .01). Fibrinogen was initially elevated in both groups and remained elevated in the splenectomy group ( P < .05). Tissue plasminogen activator, plasminogen activator inhibitor–1, and activated partial thromboplastin time were higher in splenectomy patients only at baseline ( P < .05). Baseline thromboelastography showed faster fibrin cross-linking and enhanced fibrinolysis following splenectomy ( P < .05). Only clot strength was greater at follow-up in the splenectomy group ( P < .01). Deep venous thrombosis developed in 7% of splenectomy patients and no control patients ( P = .03). Conclusions A significant difference in deep venous thrombosis formation was noted, and coagulation assays indicated persistent hypercoagulability following splenectomy for trauma.