Despite extensive clinical experience with methotrexate there is no consensus of opinion as to the ideal method of administration. This study tested the hypotheses that intermediate-dose (500-1,000 mg) methotrexate can safely by administered to outpatients as an IM injection, and that similar serum profiles of methotrexate result from IM and IV administration. Fourteen patients received 500 mg methotrexate, and nine of these received 1,000 mg as an IM injection. Methotrexate levels at 24 and 48 h were below the levels at which toxicity can be expected. Six patients received 500 mg both IM and IV and 1,000 mg both IM and IV. Serum methotrexate profiles over 48 h were similar following both IM and IV administration. This study showed no evidence of significant toxicity in terms of bone marrow, gastrointestinal, or renal impairment.