When benzo(a)pyrene (BaP) is used as the initiator in initiation-promotion assays, the topical route of administration has been shown to produce a greater epidermal tumor incidence than do other routes of administration, particularly the oral route. In addition, different strains of mice exhibit varying degrees of susceptibility to two-stage epidermal tumorigenesis using BaP. The SENCAR strain is known to be far more sensitive to epidermal tumor formation following BaP initiation than are other strains, such as the BALB/c strain. To investigate the possible contribution of distribution and binding to DNA in such route and strain differences, the distribution and macromolecular binding of (3H)BaP was examined in the skin, liver, lung, and stomach of SENCAR and BALB/c mice following topical or oral administration of BaP at time periods ranging from 0.5 to 48 h. Levels of labeled material in skin were higher, and the binding of BaP to epidermal DNA was greater following topical administration than following oral administration for mice of both strains.