Methotrexate (MTX) (1--7.6 g/m2) with leucovorin rescue was given to 19 women with stage III-IV ovarian carcinoma after induction of remission with surgical treatment and chemotherapy or after relapse. Adequate hydration with alkalinization prevented nephrotoxicity and no cumulative myelosuppression was observed. Serum MTX levels in nontoxic patients averaged 1 X 10(-6) M 24 hours following a 30-minute iv infusion of MTX at 3 g/m2. Among nontoxic women there was a 50-fold difference in the MTX level which correlated with the mean serum creatinine level. Response was assessed after 6--12 weeks of treatment by laparoscopy in patients with nonpalpable intra-abdominal tumor implants or by physical examination in patients with palpable masses. Despite the high levels of MTX achieved with the weekly schedule, only one partial response occurred among eight patients with visible or palpable metastatic lesions. Progressive disease was observed after 6--12 weeks of treatment in four of eleven women who began to receive MTX without evidence of disease or with lesions of less than 1.5 cm in diameter. MTX at the dose and schedule used in the present study appears to be of no benefit in the treatment of advanced ovarian cancer.