Study objective: We compare paracetamol with a combination of paracetamol, ibuprofen, and codeine for pain relief in acute minor musculoskeletal injuries. Methods: This was a prospective, double-blind, randomized, active-controlled, parallel-arm study at an urban tertiary hospital emergency department. Participants were aged 18 to 65 years and had acute (<48 hours) closed limb or trunk injuries with moderate pain (greater than 3/10). A single dose of 1 g of paracetamol, 400 mg of ibuprofen, and 60 mg of codeine was compared with a single dose of 1 g of paracetamol, placebo ibuprofen, and placebo codeine. The minimum detectable difference in pain was taken as 1.3. Results: Baseline characteristics and pain were similar. There were clinically detectable reductions in pain at rest at 60 minutes for paracetamol: –1.6; 95% confidence interval (CI) –2.2 to –1.1); n=59 and the combination –2.0; 95% CI –2.5 to –1; n=59; difference –0.4; 95% CI –1.1 to 0.29; P=.26. At 120 minutes, the reduction in pain was –2.4; 95% CI –3.2 to –1.6 for paracetamol (n=30) and –2.9; 95% CI –3.7 to –2.2 for the combination (n=35); difference –0.5; 95% CI –1.6 to 0.5; P=.32. Rescue analgesia was required by 4 of 59 patients in the paracetamol group and 5 of 60 in the combination group (P>.99). More participants in the combination group had adverse events: 14 of 60 versus 5 of 59 in the paracetamol group, relative risk 2.8; 95% CI 1.1 to 7.2. No adverse events were serious. Conclusion: Combining oral paracetamol, ibuprofen, and codeine as the initial treatment for pain associated with acute musculoskeletal injuries was not superior to paracetamol alone for pain reduction at 60 minutes or need for rescue analgesia, with more adverse events in the combination group.