Study objective: We compare the efficacy and adverse effects of 5 oral analgesics in emergency department (ED) patients aged 21 to 64 years with acute musculoskeletal pain. Methods: This was a randomized clinical trial conducted in 2 urban EDs. Patients received 400 mg ibuprofen/1,000 mg acetaminophen, 800 mg ibuprofen/1,000 mg acetaminophen, 30 mg codeine/300 mg acetaminophen, 5 mg hydrocodone/300 mg acetaminophen, or 5 mg oxycodone/325 mg acetaminophen. The primary outcome was change in pain before administration of medication (baseline) to 1 hour postbaseline. A numeric rating scale was used, varying from 0="no pain" to 10="worst imaginable pain." Secondary outcomes included receipt of rescue medication and adverse effects at 1 and 2 hours postbaseline. ANOVA was used to test differences in the primary outcome between treatment groups. Results: Six hundred participants, predominantly men and Latino, were enrolled. Change in pain from baseline to 60 minutes did not differ by treatment (P=.69). The mean change in pain in numeric rating scale units was 400 mg ibuprofen/1,000 mg acetaminophen 3.0 (95% confidence interval [CI] 2.6 to 3.5); 800 mg ibuprofen/1,000 mg acetaminophen 3.0 (95% CI 2.5 to 3.5), 30 mg codeine/300 mg acetaminophen 3.4 (95% CI 2.9 to 3.9), 5 mg hydrocodone/300 mg acetaminophen 3.1 (95% CI 2.7 to 3.5), and 5 mg oxycodone/325 mg acetaminophen 3.3 (95% CI 2.8 to 3.7). Rescue medication was received before 1 hour had elapsed by 2 patients receiving 400 mg ibuprofen/1,000 mg acetaminophen (1.7%), 3 patients receiving 800 mg ibuprofen/ 1,000 mg acetaminophen (2.5%), zero patients receiving 30 mg codeine/300 mg acetaminophen (0.0%), 3 patients receiving 5 mg hydrocodone/300 mg acetaminophen (2.5%), and zero patients receiving 5 mg oxycodone/325 mg acetaminophen (0.0%) (P=.21). More patients who received opioids were nauseated or vomited compared with those who did not: 6.7% versus 1.7% (5.0% difference; 95% CI 1.7% to 8.2%). The findings at 2 hours were similar. Conclusion: No analgesic was more efficacious than others 1 or 2 hours after baseline. There was significantly more nausea and vomiting among patients treated with opioids.