Epidermal growth factor (EGF) interactions with primary epidermal cells in culture were examined in BALB/c and SENCAR mice, strains resistant and sensitive, respectively, to carcinogenesis by initiation-promotion. Using low (125I-labeled EGF. Over the range tested, EGF binding increased with increasing cell density similarly in basal cells of both strains, which at similar densities bound similar amounts of EGF. Increasingly differentiated epidermal cells of both strains bound less EGF. Responses of basal and differentiating cells were dissimilar in several respects. Most notably, differentiating cells bound but failed to metabolize EGF. TPA treatment of basal cells from either strain led to a rapid, pronounced reduction in EGF binding, while treatment with retinoic add, an antipromoter in vivo, increased binding. In contrast, EGF binding by differentiating cells was much less affected by TPA treatment, and retinoic acid had no effect or was slightly inhibitory, while combined treatment was more inhibitory than either alone. Given an adequate plating density, inclusion of 1 ng EGF per ml of media significantly enhanced growth of basal cells. Because of the similarities in binding patterns between the two strains, it seems unlikely that differential responses of BALB/c and SENCAR epidermal cells to EGF and to modulators of EGF binding are involved in the differences in susceptibility of these strains to carcinogenesis.