Three hundred sixty-nine patients with femoral fractures were randomized to receive either an epidural injection of morphine 1.5 mg at the end of surgery (n = 185) or epidural saline (n = 184), after which all patients received postoperative sufentanil via IV PCA only. The primary outcome was the postoperative NRS pain score, with secondary outcomes including PCA compression frequency, total sufentanil dosage, onset time of postoperative pain, and postoperative nausea/vomiting. Outcomes were assessed on postoperative days 1, 2, 3, and 7. Overall, the results of the study revealed that in the non-morphine group, ABCB1 C1236T genotype significantly affected day-1 NRS scores, with the CC genotype associated with lower pain compared with CT and TT (P < .05). In contrast, epidural morphine eliminated genotype-related differences. In conclusion, ABCB1 C1236T appears to influence early postoperative analgesic response to sufentanil, but epidural morphine mitigates this gene–drug interaction.