OBJECTIVE To compare the relative bioavailability of low dose methotrexate (MTX) administered as tablet, oral solution, and subcutaneous (sc) injection to that of intramuscular (im) injection in patients with rheumatoid arthritis (RA). METHODS Twelve patients meeting the American College of Rheumatology criteria for RA had serial blood MTX concentration samples drawn over a 24-h period after receiving their normal weekly MTX dose. Relative bioavailability (F) of the tablet and oral solution formulations was determined by comparison of the area under the time-versus-serum-concentration curves (AUC) for the 2 different oral formulations as a percentage of the AUC for im injection. Also, relative bioavailability of the sc formulation was compared to im in 6 of the patients. RESULTS Mean F for the oral tablet was 0.85, while that for the oral solution was 0.87. Both oral formulations showed a statistically significant difference in mean F when compared to im (tablet vs im, p = 0.002, oral solution vs im, p = 0.009). No statistically significant difference, however, was found in mean relative bioavailability between tablet and solution (p = 0.744). The mean F for sc was 0.97; no statistically significant difference existed between the mean F values for the sc and im routes of administration (p = 0.657). CONCLUSIONS Our data suggest the oral solution may be substituted for tablet dosing and sc injection substituted for im. Thus, a variety of different dosing methodologies may be considered providing the most appropriate route in each patient, given issues of compliance, medication cost, and preference.