We have investigated the potential of genistein, an estrogenic component of soy, when administered neonatally, to manifest a protective effect against chemically induced mammary cancer. Female Sprague-Dawley rats were treated on Day 2, 4, and 6 postpartum with genistein or dimethylsulfoxide (vehicle). To induce mammary carcinogenesis, all animals were subsequently exposed on Day 50 postpartum to dimethylbenz(a)anthracene. Animals treated neonatally with genistein had increased latency and reduced incidence and multiplicity of mammary tumors compared with vehicle-treated animals. Cell differentiation studies in mammary whole mounts revealed that neonatal genistein treatment resulted in decreased numbers of terminal end buds and increased numbers of lobular structures. A precocious maturation of undifferentiated terminal end buds to more differentiated lobules may account for neonatal genistein treatment protecting against chemically induced mammary cancer.