To assess the role of family history in the development of multiple primary cancer, the Swedish Family-Cancer Database was used to analyze second primary cancer in patients born in 1935 to 1996 with an initial primary cancer of the colon, breast and skin (melanoma) by familial cancer in first-degree relatives. Standardized incidence ratios (SIRs) were calculated from site-, sex- and age-specific rates for all persons (offspring) born in 1935 to 1996. Familial risk (SIR) was calculated for the first and second primary cancers in offspring. A Poisson regression analysis was also performed to assess the risk factors for occurrence of second primary cancer. The familial proportion of multiple primary cancers was 29.0% (9/31) for colon, 16.3% (122/747) for female breast and 14.5% (17/117) for melanoma. Compared with all offspring, patients with family history were at a much higher and significantly increased risk for subsequent primary cancer at colon (SIR = 59.1), skin (SIR = 48.2) and female breast (SIR = 7.9). The corresponding SIRs in patients without family history were 13.8, 10.5 and 5.2 at the three sites. The ratios for incidence of second primary to first primary were highest when diagnosis age was less than 40 years. A Poisson regression analysis showed that family history was one of the major risk factors for occurrence of multiple primary cancers at colon, breast and skin. The high risk of second cancer, even in the absence of family history, would be consistent with a polygenic model of carcinogenesis. © 2001 Wiley-Liss, Inc.