Non-steroidal anti-inflammatory drugs (NSAIDs) constitute a diverse group of medications that inhibit prostaglandin synthesis. NSAIDs form the first-line pharmacological therapy in ankylosing spondylitis (AS). A number of randomized controlled trials (RCTs) support the efficacy of NSAIDs in reducing pain and improving patient function. Head-to-head comparisons have demonstrated equivalent effect of different NSAIDs in symptom control. The proposed disease-modifying potential of regular NSAID therapy is debatable and recent literature provides evidence to the contrary. Several safety concerns have been raised regarding long-term use of NSAIDs, especially an increase in cardiovascular risk. This chapter discusses the pharmacology, efficacy in treatment of AS, disease-modifying potential, and safety concerns of NSAIDs.