Background: Animal experiments indicate that environmental factors, such as cigarette smoke, can have multigenerational effects through the germline. However, there are little data on multigenerational effects of smoking in humans. We examined the associations between grandmothers’ smoking while pregnant and risk of attention-deficit/hyperactivity disorder (ADHD) in her grandchildren. Methods: Our study population included 53,653 Nurses’ Health Study II (NHS-II) participants (generation 1 [G1]), their mothers (generation 0 [G0]), and their 120,467 live-born children (generation 2 [G2]). In secondary analyses, we used data from 23,844 mothers of the nurses who were participants in the Nurses’ Mothers’ Cohort Study (NMCS), a substudy of NHS-II. Results: The prevalence of G0 smoking during the pregnancy with the G1 nurse was 25%. ADHD was diagnosed in 9,049 (7.5%) of the grandchildren (G2). Grand-maternal smoking during pregnancy was associated with increased odds of ADHD among the grandchildren (adjusted odds ratio [aOR] = 1.2; 95% confidence interval [CI] = 1.1, 1.2), independent of G1 smoking during pregnancy. In the Nurses’ Mothers’ Cohort Study, odds of ADHD increased with increasing cigarettes smoked per day by the grandmother (1–14 cigarettes: aOR = 1.1; 95% CI = 1.0, 1.2; 15+: aOR = 1.2; 95% CI = 1.0, 1.3), compared with nonsmoking grandmothers. Conclusions: Grandmother smoking during pregnancy is associated with an increased risk of ADHD among the grandchildren.