Early studies of methotrexate (MTX) in non-Hodgkin's lymphoma (NHL) and the rationale for high-dose MTX (HDMTX)-leucovorin (LV) rescue are briefly reviewed. In Phase II studies at the Dana-Farber Cancer Institute, published in 1977, HDMTX-LV (1-7.5 g/m2 MTX) was given to 12 patients with diffuse large cell lymphoma (DLCL) failing prior chemotherapy. Five (24%) patients responded, including 2 with complete remissions (CR). HDMTX, bleomycin, doxorubicin, cyclophosphamide, vincristine and dexamethasone (M-BACOD) was developed (MTX = 3 g/m2 on day 14 of each cycle) in an effort to reduce relapse between cycles of chemotherapy and also to prevent subsequent CNS relapse. Results in 101 patients published in 1983 showed CR in 72% with a projected survival of 59% out to 5 years. For CR patients, survival was 85% with disease-free survival 74%. In order to render the program more feasible, as well as reduce potential toxicity and cost, moderate-dose MTX-LV (200 mg/m2 MTX on day 7 and 14) was substituted for HDMTX-LV. Preliminary results from this new protocol, moderate-dose MTX, bleomycin, doxorubicin, cyclophosphamide, vincristine and dexamethasone (m-BACOD), as of November 1985 in 80 patients, show CR in 60 (75%) patients. The 2-year survival is 70% with a projected 4-year survival of 60%. Review of both protocols shows similar results including rate of CNS relapse (about 5%). In a multivariate analysis, 3 prognostic groups have been defined, which will allow for new therapeutic strategies in future studies. Prospective randomized trials will be required to determine the role, dose, and schedule of MTX-LV in DLCL.