We conducted a case-control study of childhood leukemia in Korea to evaluate the effects of smoking and CYP1A1 genotype on risk. Histologically confirmed childhood leukemia cases (n=166) and non-cancer controls (n=166) frequency-matched for sex and age were recruited from three teaching hospitals between April 2003 and May 2005. Information on demographics and smoking exposures were collected by trained interviewers. Five selected single nucleotide polymorphisms (SNPs) in CYP1A1 (i.e., -17961T>C, -9893G>A, I462V, 1188C>T, and 11599C>G) were genotyped and haplotypes were estimated by the Expectation-Maximization method.  Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression, adjusting for age, father's education, and the child's birth weight. Paternal smoking at home (OR=1.7, 95% CI=1.07-2.75) and the number of smokers in the home (P_trend=0.05) increased the risk of childhood leukemia. The distribution of the five individual SNPs or haplotypes did not differ significantly between cases and controls. However, in diplotype analyses, we observed significant interactions between smoking and CYP1A1 genotype. Among CGACC (-) individuals but not among those who were CGACC (+), father's smoking at home (OR=2.2, 95% CI=1.24-3.92) and the presence of at least one smoker in the home (OR=1.9, 95% CI=1.05-3.40) significantly increased the risk of childhood leukemia (P_interaction=0.15 and 0.12, respectively). These interactive effects became stronger when we restricted our analyses to cases with acute lymphoblastic leukemia (P_interaction=0.04 and 0.03, respectively). Our results suggest that paternal smoking is a risk factor for childhood leukemia and interact with CYP1A1 genotype in the development of childhood leukemia in Korea.