Non-steroidal anti-inflammatory drugs (NSAIDs) play different roles in the management of patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). In RA there is minimal evidence that NSAIDs are able to alter the course of disease or prevent joint destruction and, therefore, they should mostly be used as a short-term bridging therapy. In contrast to RA, in AS NSAIDs are considered as a cornerstone of the treatment not only because of a high symptomatic efficacy, but also because they might even retard osteoproliferation and radiographic progression. Considering younger age of AS patients and lower prevalence of comorbidities, they are probably at lower risk for cardiovascular and gastrointestinal side effects of short- and long-term NSAID therapy in comparison to RA.