Osteoarthritis is a major public health burden. The incidence of osteoarthritis increases with advancing age. Symptomatic treatments aimed at alleviating the pain and thereby restoring joint function form the basis of the treatment. The chronic course requires long-term treatment with special attention to minimizing the side effects of drugs. Acetaminophen has a good risk/benefit ratio that has prompted international consensus panels to recommend its use as first-line therapy in dosages of up to 4 g/day. This review discusses safety and efficacy data from randomized double-blind trials of acetaminophen used to alleviate pain caused by osteoarthritis.