In order to compare the relative bioavailability of orally administered methotrexate (MTX) with i.m. administration in patients with rheumatoid arthritis, we compared the pharmacokinetics of MTX at both the usual starting dose of 7.5 mg and at higher established maintenance dosages in 21 patients. Pharmacokinetic measures were repeated approximately 6 and 18 months after baseline while patients consumed their usual maintenance doses of MTX (17.0 +/- 3.8 mg). The relative bioavailability of the usual maintenance dose of MTX was reduced by 13.5% compared with the initial dose of 7.5 mg (P = 0.026). Area under the serum concentration vs time curve (AUC) was significantly reduced with oral vs i.m. administration at usual maintenance doses (decrease of 0.729 mumol.h/l by oral administration, P = 0.027), but not at a 7.5 mg dose of MTX. Clinicians using MTX should not assume constant and complete bioavailability across the dose range used to treat patients with rheumatoid arthritis. Our observations explain the reported clinical success of switching from an oral to a parenteral route of administration in patients receiving maintenance doses of MTX.