The role of a family history of cancer in the etiology of childhood hematopoietic malignancies was investigated using the data from the ESCALE study. ESCALE, a population-based case–control study, was carried out in France over the period, 2003–2004. A total of 773 cases of acute leukemia (AL), 130 of Hodgkin's lymphoma (HL), 163 of non-Hodgkin's lymphoma (NHL) and 1,681 population-based controls were included. The controls were randomly selected from the French population and were frequency matched with the cases on age and gender. Cancer history in first- and second-degree relatives was reported by the mothers in a structured telephone questionnaire that was the same for the cases and controls. Odds ratios (ORs) were estimated using an unconditional regression model taking into account the stratification variables and potential confounders. A family history of cancer was associated with an increased risk of HL (OR = 1.5 [1.0–2.2]) and NHL (OR = 1.8 [1.3–2.5]), but not AL (OR = 1.0 [0.9–1.2]). The ORs were higher when at least 2 relatives had a history of cancer or when 1 case occurred before age 46 years. Only HL was significantly associated with a family history of hematopoietic malignancies (OR = 2.0 [1.0–3.8]), mainly because of a significant association with a history of HL (OR = 5.4 [1.3–22]). In conclusion, the study findings support the hypothesis of familial susceptibility to childhood lymphoma, but do not suggest familial susceptibility to childhood AL. © 2007 Wiley-Liss, Inc.