In this double-blind, parallel-group study, we compared 3 oxymorphone immediate-release (IR) doses with placebo for efficacy and with oxycodone IR and placebo for safety in patients with acute moderate-to-severe postsurgical pain. During the single-dose phase (n = 300), patients received oxymorphone IR 10, 20, or 30 mg; oxycodone IR 10 mg; or placebo. All oxymorphone IR doses were superior for providing pain relief for 8 h (P < 0.05), with a significant analgesic dose response (P < 0.001). Significant pain intensity differences occurred by 45 min (20- and 30-mg doses; P < 0.05). Discontinuations for lack of efficacy totaled 42% among placebo-treated patients and 27% among those treated with oxymorphone IR. Patients requiring rescue medication after 3 h were allowed to receive additional study drug every 4 to 6 h as needed for the multiple-dose phase (n = 164). All oxymorphone groups maintained analgesia for 48 h. The median dosing interval was >9.5 h for oxymorphone IR 30 mg and > or =7 h for the other groups. Opioid-related adverse events, similar among groups, were generally mild or moderate. Oxymorphone IR 10, 20, or 30 mg provided significant dose-related pain relief compared with placebo, and this relief was maintained over several days with a safety profile comparable to that of oxycodone IR.