Non-opioid analgesics are often administered to emergency department (ED) patients with musculoskeletal pain but if inadequate, opioids are given with associated potential adverse events. We tested the hypothesis that the reduction in pain scores with the combination of ibuprofen and acetaminophen would be at least 15 mm greater than with either of the agents alone. We conducted a double-blind, randomized, controlled trial of adult ED patients with acute musculoskeletal pain. Patients were randomized to oral ibuprofen 800 mg, acetaminophen 1 g, or their combination. Pain scores across the groups were compared with repeated measures analysis of variance at 20, 40, and 60 minutes. A sample of 30 patients in each group had 80% power to detect a 15 mm difference in pain scores across the groups (α = .05). Thirty patients were randomized to each study group. Mean (SD) age was 36 (15), 54% were male, 73% were white, and 13% were Hispanic. Groups were well balanced in baseline characteristics including initial pain scores (59, 61, and 62 for ibuprofen, acetaminophen, and their combination). Pain decreased over the one hour study period for all groups (P < .001) with mean (SD) scores about 20 mm lower on the Visual Analogue Scale than the mean initial score. However, there was no significant difference among treatments (P = .59). The need for rescue analgesics was similar across groups. We conclude that the combination of ibuprofen and acetaminophen did not reduce pain scores or the need for rescue analgesics compared with either agent alone in ED patients with pain secondary to acute musculoskeletal injuries.