Heterozygous female mice carrying a targeted mutation of the Ets2 transcription factor gene were mated with a mouse strain that develops mammary tumors due to the expression of the polyoma virus middle T oncogene. Tumors from females with only one wild-type Ets2 gene were approximately one-half the size of tumors from controls. The smaller size of the tumors was correlated with a more differentiated state of early hyperplastic growths and not to differential growth of the frank tumors or to decreased middle T gene expression. Ets2 may regulate the progression of these aggressive mammary tumors.