Most cells deficient in 3-methyladenine (3MeA) DNA glycosylase become sensitive to the lethal and clastogenic effects of alkylating agents. Surprisingly, myeloid progenitor bone marrow (BM) cells derived from Aag -/- mice were more resistant than those from wild-type mice to the cytotoxic effects of several alkylating agents. Moreover, an alkylation-resistant phenotype was observed in vivo using the BM micronucleus assay as a measure of chromosome damage. Flow cytometry indicated that in vivo alkylation resistance in Aag null BM cells may be restricted to cells of the myeloid lineage. These results show that in particular cell types, the initiation of base excision repair is more lethal to the cell than leaving the damaged bases unrepaired by Aag.