The association between maternal smoking during pregnancy and childhood cancer was investigated using prospectively-collected data from a cohort of 44,621 pregnant women who gave birth to 54,795 live born children. The children were followed a median of 88 months. Cases of cancer had a histologic diagnosis and/or a compatible clinical course. There were 51 children with cancer (17 leukemia, 8 CNS tumors, 7 Wilms tumor, 6 neuroblastoma, 5 lymphoma, 3 retinoblastoma, 2 rhabdomyosarcoma, 2 hepatoblastoma, 1 fibrosarcoma); 83% of still-borns were autopsied and none had cancer. The cumulative incidence of cancer to age 7½ years was 1.1/1000. Maternal smoking was determined at each prenatal visit; 52% of mothers reported smoking at one or more visits. By age 7½, cancer occurred in 1.4/1000 children whose mothers did not smoke during pregnancy, compared to 0.9/1000 children whose mothers smoked(p=0.15 by logrank test); the hazard ratio was 0.67 (95% CI 0.38-1.17). There was no dose-response effect of smoking compared to non-smokers (hazard ratio for ½ pack/day or less=0.45, over ½ pack/day=0.83, p for trend=0.39). The hazard ratio for leukemia among children whose mothers smoked was 0.82 (0.31-2.11); the hazard ratio for cancers other than leukemia was 0.60 (0.30-1.20). Adjustment for race, date of birth, parity, maternal education and x-ray exposure did not materially change the odds ratios. Although the relatively small number of cases precluded extensive study of individual types of cancer, we conclude that maternal smoking in pregnancy is not associated with an increased risk of childhood cancer in this cohort.