The aim of this blinded, randomised, multicentre study was to compare the tolerability of aspirin, paracetamol and ibuprofen in common pain resulting from musculoskeletal conditions (MSC) in general practice with patients with other non-MSC pain conditions. Patients took aspirin, paracetamol (both up to 3g daily) or ibuprofen (up to 1.2g daily) for up to 7 days. The main outcome was the rate of significant adverse events (SGAE). Four thousand two hundred and ninety one patients with MSC were evaluable (1436 aspirin, 1423 paracetamol, 1432 ibuprofen) and 4101 (95.5%) were per-protocol. A group of 4342 patients included for other (non-MSC) mild to moderate pain conditions was used for comparison. In the MSC group, SGAE were reported by 20.5% of patients with aspirin, 17.0% with paracetamol and 15.0% with ibuprofen. Ibuprofen was statistically equivalent to paracetamol and better tolerated than aspirin (p <0.0001). Ibuprofen was associated with fewer digestive system AE (4.4%) than aspirin (8.6%, p<0.0001) and paracetamol (6.5%, p <0.02). The non-MSC group showed similar intertreatment differences, but experienced fewer SGAE. No serious digestive events were observed with any of the three treatments in either group. These results show that in patients with mild to moderate pain resulting from MSC, ibuprofen given in OTC doses for 6 days is as well tolerated as paracetamol and better tolerated than aspirin.