The human H-ras oncogene induces cell degeneration and diabetes when expressed in pancreatic beta-cells in transgenic mice. The disease develops predominantly in male mice between 5-8 months of age. Most transgenic female mice do not manifest this phenotype, even at much greater ages. However, ovariectomy induces female beta-cell degeneration similar to that in the males. In contrast, castration or the presence of the testicular feminization mutation do not alter the course of the disease in males. Treatment of males and ovariectomized females with estrogen prevents the development of diabetes. These results suggest that testicular androgens and a functional testosterone receptor are not required for the increased susceptibility of male beta-cells to the effects of the Ras oncoprotein, and that the relative resistance of female beta-cells is mediated by estrogen. In addition, a genetic component of female beta-cell resistance to Ras is revealed by crossing the transgenic mice with C3HeB/FeJ mice, which results in a pronounced increase in the incidence of female diabetes.