Background: Whether parental drinking and smoking during pregnancy are associated with an increased risk of cancer in offspring is controversial. There are some indications that maternal alcohol consumption is associated with an elevated risk of acute myeloid leukemia (AML) appearing in very young children. Evidence for an association between maternal smoking during pregnancy and risk of leukemia in offspring has been inconsistent. Purpose: Using data from a Childrens Cancer Group case-control study, we evaluated relationships between infant leukemia risk and parental alcohol consumption and/or cigarette smoking during pregnancy or during the month prior to it. Methods: Three hundred two leukemia cases (203 acute lymphoid leukemias [ALLs], 88 AMLs, and 11 other leukemia types) diagnosed in children at 18 months of age or younger and 558 individually matched, regional (i.e., same telephone area code and exchange number) controls were included in the analysis. Information concerning parental alcohol consumption and smoking behavior during the index pregnancy and during the month prior to it was collected by telephone interviews with the mothers of all case and control subjects and the fathers of 250 case and 361 control subjects. Odds ratios (ORs) were used to measure the risk of infant leukemia associated with parental smoking and drinking; tests for trend were used to assess dose- response relationships. The data were analyzed further after stratifying the leukemia cases according to histologic and morphologic types. Reported P values are from two-sided tests of statistical significance. Results: Maternal drinking during pregnancy (compared with not drinking) was associated with ORs of 1.43 (95% confidence interval [CI] = 1.00-2.04) for ALL and 2.64 (95% CI = 1.36-5.06) for AML. A dose-response relationship was observed for total maternal alcohol consumption during pregnancy and risk of AML (P<.01). Alcohol-related risk appeared to he most pronounced for children who developed AML with a morphology of M1 (myeloblastic with minimal maturation) or M2 (myeloblastic with maturation) (OR = 7.62; 95% CI = 2.03- 28.64). Paternal alcohol consumption did not confer an increased risk of infant leukemia. Maternal smoking during pregnancy (compared with not smoking) was negatively associated with infant leukemia risk (OR = 0.66 and 95% CI = 0.46-0.94 for total leukemia; OR = 0.45 and 95% CI = 0.21-0.96 for AML), whereas paternal smoking 1 month prior to pregnancy (compared with not smoking during the same period) was related to an elevated risk of ALL (OR = 1.56; 95% CI = 1.03-2.36). Conclusions: Maternal alcohol consumption during pregnancy increases the risk of infant leukemia, especially AML. Maternal smoking, however, does not elevate risk for either AML or ALL. Implication: The data suggest that in utero exposure to alcohol may contribute to leukemogenesis involving myeloid cells.