OBJECTIVE - To evaluate to what extent the association between family history of diabetes and risk of type 2 diabetes can be explained by excess adiposity and lifestyle risk factors. RESEARCH DESIGN AND METHODS - We analyzed data from 73,227 women who participated in the Nurses' Health Study cohort. A family history of diabetes was defined as having at least one first-degree family member with diabetes. Lifestyle factors, weight, and height were assessed by using validated questionnaires, and BMI was calculated. The relative risk of type 2 diabetes was estimated using Cox proportional hazards analysis. RESULTS - We documented 5,101 cases of type 2 diabetes during 20 years of follow-up. The age-adjusted relative risk of type 2 diabetes in participants with a family history was 2.27 (95% CI 2.14-2.40) compared with the risk in those without a family history of diabetes. Participants with a family history of diabetes had a higher BMI and were more likely to have a parental history of obesity. BMI explained 21.1% (19.4-22.9) of the association between family history of diabetes and risk of type 2 diabetes. Intakes of red meat, alcohol, and sugar-sweetened beverages explained 1.1% (0.8-1.3), 4.8% (4.3-5.3), and 2.8% (2.4-3.2) of this association, respectively. CONCLUSIONS - These results suggest that excess adiposity and, to a lesser extent, specific dietary habits can explain a substantial part of the association between having a family history of diabetes and risk of type 2 diabetes. © 2010 by the American Diabetes Association.