Genetic and environmental hypotheses that might explain the patterns of occurrence of breast cancer and associated cancer in 18 large families at high risk of the disease were tested with the use of segregation analysis. For 16 pedigrees, results were consistent with the hypothesis that breast cancer has a genetic etiology. In 2 other families, breast cancer appeared more likely to have an environmental origin. Breast cancer susceptibility is best explained by hypotheses that postulate autosomal dominant susceptibility alleles in 10 families with primarily premenopausal breast cancer and ovarian cancer, in 4 families with primarily postmenopausal breast cancer, and in 2 families with breast cancer, brain tumor, sarcoma, leukemia, and adrenocortical carcinoma in children and young adults. In an accompanying paper, genetic susceptibility in the first 2 groups of families is further explored with the use of linkage analysis.