DepoDur^® (liposome-encapsulated morphine) is a single-dose epidural analgesic providing postoperative pain relief for up to 48 hours. The efficacy of DepoDur^® combined with local anesthetics for postoperative analgesia is unknown. This study assessed the efficacy of DepoDur^® (15 mg) alone and following epidural bupivacaine. DepoDur^® or placebo was administered 15, 30, or 60 minutes after a preoperative dose of 20ml 0.25% bupivacaine. Various pain assessments were made postoperatively and adverse events (AEs) were recorded. For all efficacy endpoints, DepoDur^® with bupivacaine was superior to bupivacaine alone. Combined treatment was not different from DepoDur^® alone. Mean ± SD cumulative fentanyl use ranged from 552±748 µg to 985±1333 µg in the DepoDur^® groups vs 3817±3844 µg with bupivacaine alone (P<0.05). Mean ±SD 48-hour area under the pain intensity–time curves with activity were lower (P<0.05) in DepoDur^®-treated patients compared to bupivacaine alone. More patients and surgeons rated pain control as good or very good in the DepoDur^® groups compared with bupivacaine alone (P<0.05). AEs were lowest with bupivacaine alone and similar across DepoDur^® groups. Nausea and vomiting were more frequent after DepoDur^® with bupivacaine (75% and 37%) compared to DepoDur^® (59% and 19%) or bupivacaine alone (52% and 13%). Respiratory depression related to DepoDur^® occurred in 1 patient receiving DepoDur^® alone versus 6 patients receiving DepoDur^® with bupivacaine. In summary, a single perioperative dose of DepoDur^® appears equally effective when administered alone or with bupivacaine but the combination may increase some AEs such as nausea and vomiting. Supported by Endo Pharmaceuticals Inc. and SkyePharma Inc.