Toxicity Index scores were computed from symptoms, laboratory abnormalities, and hospitalizations attributed to nonsteroidal antiinflammatory drug (NSAID) therapy in 2,747 patients with rheumatoid arthritis receiving 5,642 courses of 11 NSAIDs over 8,481 patient-years. Substantial differences in overall toxicity were found, the differences between drugs often being clinically significant (2-3 times as toxic) and highly statistically significant. The results strengthened after adjustment for differing patient characteristics, held generally across multiple ARAMIS (Arthritis, Rheumatism, and Aging Medical Information System) data bank centers, and persisted after use of different techniques for the weighting of side effects. The most toxic side effects were experienced by patients taking indomethacin (mean ± SEM score 3.99 ± 0.58), tolmetin sodium (3.96 ± 0.74), and meclofenamate sodium (3.86 ± 0.66). Least toxic were coated or buffered aspirin (1.19 ± 0.10), salsalate (1.28 ± 0.34), and ibuprofen (1.94 ± 0.43). The most toxic drugs were generally taken in the lowest relative doses. There are statistical differences in overall toxicity between different NSAIDs as used in rheumatoid arthritis, and these differences are both clinically and statistically significant.