Twenty-three patients with advanced carcinoma were treated with 131 courses of high-dose oral methotrexate (MTX), sequenced at 24 hours with 5-FU iv and subsequent leucovorin rescue. The 30% incidence of toxicity was predominantly mild to moderate mucositis and myelosuppression. Trough and peak serum MTX levels demonstrated that micromolar concentrations were sustained greater than 24 hours. Toxicity correlated with shorter re-treatment intervals and not with serum MTX levels. This regimen can be safely and conveniently administered to an outpatient population and deserves further assessment in phase II trials.