This open-label, serial-cohort pilot study evaluated DepoDur, a new, single-dose, extended-release epidural morphine (EREM) for pain control after hip arthroplasty. Single-dose EREM (10-30 mg) or a single dose of standard morphine sulfate (MS) (5 mg) was administered before surgery and spinal anesthesia. Among the 39 patients enrolled, total 48-hour supplemental fentanyl use was lower (P = 0.011 overall treatment) and median time to first postoperative fentanyl use was three- to six-fold longer (P < 0.001 overall treatment), among 10-, 20-, and 30-mg single-dose EREM patients versus MS patients. EREM patients reported higher levels of satisfaction with pain intensity scores comparable to MS patients. Safety results were similar between groups. Single-dose EREM was generally safe and effective for treating postoperative pain and reduced the need for supplemental analgesia.