Pharmacokinetic drug interaction between methotrexate (MTX) and nonsteroidal anti-inflammatory drugs (NSAID) has been implicated in several case reports of MTX related toxicity. We therefore studied the kinetics of low dose (15 mg) oral MTX with and without concomitant NSAID therapy after preliminary determination of the systemic bioavailability of commercial tablets. Fourteen patients with rheumatoid arthritis, age range 44-77 years, participated in paired kinetic studies performed 1-4 weeks apart. The Abbott TDx fluorescence polarization immunoassay was used to measure serum levels and urinary excretion of MTX over 72 h after a single dose. The mean systemic bioavailability was 73% for the 15 mg oral dose. Area under the serum concentration versus time curve for a 50 mg oral dose was 1.1-2.7 times that of the 15 mg oral dose indicating dose dependent absorption. Mean kinetic variables after oral MTX did not differ significantly with and without NSAID therapy despite apparent interactions in individual patients. Renal clearance of MTX correlated with creatinine clearance (r = 0.8, p less than 0.01).