To test the concept that protection of bone marrow progenitor cells via introduction of a drug resistance gene would allow larger and curative doses of chemotherapy to be administered, we used mice bearing a transplanted breast cancer as a model system. Mice bearing the E0771 tumor were treated with lethal doses of cyclophosphamide (CPA) and rescued from toxicity by administration of bone marrow transduced with a mutant dihydrofolate reductase (DHFR) cDNA (Ser-31) in a retroviral construct. Animals receiving marrow not transduced with mutant DHFR cDNA died from methotrexate (MTX) toxicity, whereas mice transduced with mutant DHFR cDNA containing marrow were able to tolerate MTX treatment post-transplant; 44% of the mice had no demonstrable tumor when sacrificed on day 52. Another control group of mice treated with CPA and transplanted but not treated with MTX post-transplant succumbed to tumor regrowth. These data provide a strong rationale for the use of drug resistance genes to protect marrow from drug toxicity because the increase in dose tolerated may result in an improved cure rate of chemosensitive tumors.