Fifteen randomized controlled trials enrolling patients with either hip or knee osteoarthritis or patients with knee osteoarthritis only were selected for meta-analysis comparing the efficacy of non-steroidal anti-inflammatory drug (NSAID) therapy and acetaminophen for reducing pain. Subgroup analyses for various methodological and clinical factors were planned to investigate their impact on heterogeneity. Overall, NSAID therapy resulted in significantly lower pain in comparison to acetaminophen. Statistical significance favouring NSAIDs over acetaminophen was also demonstrated in all subgroup analyses performed.