A case-control study nested within a large cohort, the American Cancer Society Cancer Prevention Study-1, was conducted to test associations between a family history of cancer and cancer mortality in women. By using logistic regression, the authors analyzed family history, as reported by 429,483 women enrolled in 1959, relative to subsequent mortality through 1972 from cancer within and across multiple sites. The associations between family history and cancer mortality were generally stronger within cancer sites than across cancer sites. Within-site associations were found for breast cancer (odds ratio (OR) = 1.9), colorectal cancer (OR = 1.6), stomach cancer (OR = 1.9), and lung cancer (OR = 1.7). Across-site associations were observed for a family history of 1) breast cancer as a risk factor for ovarian cancer mortality (OR = 1.6), 2) stomach cancer as a risk factor for ovarian cancer mortality (OR = 1.5), and 3) uterine cancer as a risk factor for pancreatic cancer mortality (OR = 1.6). A general pattern of positive associations was observed between a family history of cancer at several sites and subsequent death from pancreatic cancer. These findings support the growing body of evidence from cancer genetics suggesting that inherited cancer-susceptibility genes increase the risk for cancer at many sites and are not specific to cancer risk within a single site.