CONTEXT Previous epidemiological, animal, and human cognitive neuroscience research suggests that maternal smoking during pregnancy (SDP) causes increased risk of substance use/problems in offspring. OBJECTIVE To determine the extent to which the association between SDP and offspring substance use/problems depends on confounded familial background factors by using a quasi-experimental design. DESIGN We used 2 separate samples from the United States and Sweden. The analyses prospectively predicted multiple indices of substance use and problems while controlling for statistical covariates and comparing differentially exposed siblings to minimize confounding. SETTING Offspring of a representative sample of women in the United States (sample 1) and the total Swedish population born during the period from January 1, 1983, to December 31, 1995 (sample 2). PATIENTS OR OTHER PARTICIPANTS Adolescent offspring of the women in the National Longitudinal Survey of Youth 1979 (n = 6904) and all offspring born in Sweden during the 13-year period (n = 1 187 360). MAIN OUTCOME MEASURES Self-reported adolescent alcohol, cigarette, and marijuana use and early onset (before 14 years of age) of each substance (sample 1) and substance-related convictions and hospitalizations for an alcohol- or other drug-related problem (sample 2). RESULTS The same pattern emerged for each index of substance use/problems across the 2 samples. At the population level, maternal SDP predicted every measure of offspring substance use/problems in both samples, ranging from adolescent alcohol use (hazard ratio [HR]moderate, 1.32 [95% CI, 1.22-1.43]; HRhigh, 1.33 [1.17-1.53]) to a narcotics-related conviction (HRmoderate, 2.23 [2.14-2.31]; HRhigh, 2.97 [2.86-3.09]). When comparing differentially exposed siblings to minimize genetic and environmental confounds, however, the association between SDP and each measure of substance use/problems was minimal and not statistically significant. CONCLUSIONS The association between maternal SDP and offspring substance use/problems is likely due to familial background factors, not a causal influence, because siblings have similar rates of substance use and problems regardless of their specific exposure to SDP.