Objective The objective of this study was to assess the effectiveness of a low‐dose intravenous S‐ketamine treatment on refractory pain in patients with Complex Regional Pain Syndrome (CRPS). Methods In this retrospective study, patients with CRPS who received intravenous S‐ketamine from March 2010 to April 2019 were included. According to our inpatient protocol, S‐ketamine dose was increased until pain reduction was achieved or side effects were observed. Maximum dose was 14 mg/h and treatment duration was 7 days. Primary outcome parameters were pain scores (Numeric Rating Scale) at baseline (T0), end of infusion (T1), and approximately 4 weeks postinfusion (T2). Patients were categorized as responder/nonresponder at T1 and T2. Patients were considered a responder in case there was pain score reduction of greater than or equal to 2 points or if treatment was reported as successful. Results Forty‐eight patients were included. Mean disease duration was 5 years (interquartile range IQR = 6 years). Median pain score significantly decreased from 8 (IQR = 2) at T0 to 6 (IQR = 4) at T1 (p < 0.001). At T1, 62% of the patients were responders. At T2, 48% of the patients remained a responder. A significant proportion of the responders at T1 turned into nonresponders at T2 (p = 0.03). Conclusion In a group of patients with CRPS with refractory pain, low‐dose intravenous S‐ketamine treatment resulted in effective pain relief during infusion. Although a significant proportion of initial responders became nonresponders at follow‐up, half of the patients were still a responder at ~ 4 weeks postinfusion. Further research is needed to investigate mechanisms responsible for pain relief by S‐ketamine infusions and to ascertain possible predictors of response to the treatment.