A small proportion of childhood cancer is attributable to known hereditary syndromes, but whether there is any familial component to the remainder remains uncertain. We explored familial aggregation of cancer in a population-based case-control study using genealogical record linkage and designed to overcome limitations of previous studies. Subjects were selected from the Utah Population Database. We compared risk of cancer in adult first-degree relatives of children who were diagnosed with cancer with the risk in relatives of children who had not had a cancer diagnosed. We identified 1,894 childhood cancer cases and 3,788 controls; 7,467 relatives of cases and 14,498 relatives of controls were included in the analysis. Relatives of children with cancer had a higher risk of cancer in adulthood than relatives of children without cancer [odds ratio (OR) 1.31, 95% confidence interval (CI) 1.11-1.56]; this was restricted to mothers and siblings and was not evident in fathers. Familial aggregation appeared stronger among relatives of cases diagnosed before 5 years of age (OR 1.48, 95% CI 1.13-1.95) than among relatives of cases who were older when diagnosed (OR 1.22, 95% CI 0.98-1.51). These findings provide evidence of a generalized excess of cancer in the mothers and siblings of children with cancer. The tendency for risk to be higher in the relatives of children who were younger at cancer diagnosis should be investigated in other large data sets. The excesses of thyroid cancer in parents of children with cancer and of any cancer in relatives of children with leukemia merit further investigation.The causes of childhood cancer are largely unknown. A small proportion of cases are attributable to known hereditary cancer syndromes, but whether there is any familial component to the remainder remains uncertain. Understanding familial risks may help to further elucidate etiology and/or identify the need to screen family members.Little 1 reviewed much of the already extensive literature published to 1997 on aggregation of cancer among firstdegree relatives of children with cancer. Many of these studies involved a relatively small number of cases, and Little concluded that there was no strong evidence of familial risks in parents or siblings for most of the common types of childhood cancer. Since then, several large studies of cancer risk in first-degree relatives of children with cancers of all types have emerged from the Nordic countries, 2 the United Kingdom, 3 the United States 4 and Italy. 5,6 Analyses of risk for many types of childhood cancer have also been published from the Swedish Family Cancer Database. 7-9 There has been broad agreement that overall the risk of childhood cancer in the siblings of children with cancer is moderately increased. 2,10,11 In a population-based study in the Nordic countries, there was a small increase in the risk of cancer in siblings of all ages combined, but this was entirely accounted for by known familial cancer syndromes. 2 Conversely, a North American study of the siblings of 5-y...