The RNA encoded by the 3' untranslated region of the prohibitin gene arrests cell proliferation by blocking the transition between the G1 and S phases of the cell cycle. The product of a variant allele (T allele) is inactive. We did a case-control study of prohibitin genotype in 205 women with breast cancer and 1046 healthy controls. The results showed an association between the T allele and breast cancer in women who reported a first-degree relative with the disease (odds ratio 2.5, p=0.005). An even stronger association was found in a subset of women diagnosed at or before age 50 years (4.8, p=0.003). These data suggest that prohibitin genotyping has value in assessing risk of breast cancer in women aged 50 years or younger with at least one first-degree relative with the disease.