IMPORTANCE: Several studies report an association between maternal smoking during pregnancy and offspring conduct disorder. However, past research evidences difficulty in disaggregating prenatal environmental influences from genetic and postnatal environmental influences. OBJECTIVE: To examine the relationship between maternal smoking during pregnancy and offspring conduct problems among children reared by genetically related mothers and genetically unrelated mothers. DESIGN, SETTING, AND PARTICIPANTS: The following 3 studies using distinct but complementary research designs were used: The Christchurch Health and Development Study (a longitudinal cohort study that includes biological and adopted children), the Early Growth and Development Study (a longitudinal adoption-at-birth study), and the Cardiff IVF (In Vitro Fertilization) Study (an adoption-at-conception study among genetically related families and genetically unrelated families). Maternal smoking during pregnancy was measured as the mean number of cigarettes per day (0, 1-9, or ≥10) smoked during pregnancy. Possible covariates were controlled for in the analyses, including child sex, birth weight, race/ethnicity, placement age, and breastfeeding, as well as maternal education and maternal age at birth and family breakdown, parenting practices, and family socioeconomic status. MAIN OUTCOMES AND MEASURE: Offspring conduct problems (age range, 4-10 years) reported by parents or teachers using the behavior rating scales by Rutter and Conners, the Child Behavior Checklist and the Children's Behavior Questionnaire Short Form, and the Strengths and Difficulties Questionnaire. RESULTS: A significant association between maternal smoking during pregnancy and offspring conduct problems was observed among children reared by genetically related mothers and genetically unrelated mothers. Results from ameta-analysis affirmed this pattern of findings across pooled study samples. CONCLUSIONS AND RELEVANCE: Findings across 3 studies using a complement of genetically sensitive research designs suggest that smoking during pregnancy is a prenatal risk factor for offspring conduct problems when controlling for specific perinatal and postnatal confounding factors.