The effects of three non-steroidal anti-inflammatory drugs (NSAIDs) on the pharmacokinetics of methotrexate were studied in 10 patients with rheumatoid arthritis. Ketoprofen (3 mg kg-1 day-1), flurbiprofen (3 mg kg-1 day-1), piroxicam (20 mg day-1), or a non-NSAID control (paracetamol/acetaminophen) were administered to patients for at least 6 days (13 days in the case of piroxicam to establish steady state) in a randomized crossover design prior to receiving a weekly oral dose of methotrexate. In the non-NSAID control portion of the study, MTX oral clearance (CLo) was 11.0 +/- 3.9 l h-1, renal clearance (CLR) was 7.9 +/- 2.8 l h-1, percent excreted unchanged was 72 +2- 19% and fraction unbound (fu) was 0.54 +/- 0.11. Values of oral clearance, renal clearance, fraction unbound and percentage excreted unchanged of methotrexate varied no more than 12.2% from non-NSAID control during concomitant administration of ketoprofen, flurbiprofen or piroxicam and were not statistically different from non-NSAID control. In contrast to other NSAIDs such as ibuprofen and salicylates, ketoprofen, flurbiprofen or piroxicam in clinically relevant doses do not appear to affect methotrexate disposition and may be used safely in combination with methotrexate.