Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed drugs and are responsible for approximately one-quarter of all adverse drug reaction reports. NSAIDs are widely prescribed for patients with the rheumatic disease-a population at increased risk for serious gastrointestinal (GI) complications. Topical administration of NSAIDs offers the advantage of local, enhanced drug delivery to affected tissues with a reduced incidence of systemic adverse effects, such as peptic ulcer disease and GI hemorrhage. NSAIDs administered topically penetrate slowly and in small quantities into the systemic circulation. Product formulation may have a dramatic impact, not only on absorption rates but also on penetration depth. Concentrations achieved in the muscle tissue below the site of application are variable but are at least equivalent to that obtained with oral administration. Absorption may be strongly influenced by individual skin properties. Topically applied NSAIDs have a superior safety profile to oral formulations. GI adverse drug reactions are rare with topically applied NSAIDs, compared with a 15% incidence reported for oral NSAIDs.