CONTEXT: The risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (DM) associated with obesity appears to be influenced by the coexistence of other metabolic abnormalities. OBJECTIVE: We examined the risk of developing CVD and DM in metabolically healthy obese (MHO) and metabolically unhealthy normal weight (MUH-NW) individuals. DESIGN AND SETTING: We analyzed prospective data of the San Antonio Heart Study, a population-based study among Mexican Americans and non-Hispanic whites (median follow-up, 7.4 y). PARTICIPANTS: Incident DM and CVD were assessed in 2814 and 3700 participants aged 25 to 64 years, respectively. MAIN MEASURES: MHO was defined as obesity (body mass index ≥ 30 kg/m(2)) with no more than one metabolic abnormality, and MUH-NW was defined as body mass index <25 kg/m(2) with two or more abnormalities. RESULTS: In logistic regression models, BMI was associated with incident DM after controlling for demographics, family history of DM, and fasting glucose (odds ratio × 1 SD, 1.7 [95% CI, 1.5-2.0]). Both MUH-NW and MHO individuals had an increased DM risk (2.5 [1.1-5.6] and 3.9 [2.0-7.4], respectively). Similarly, BMI was related to incident CVD after adjusting for demographics and Framingham risk score (1.3 [1.1-1.6]). Incident CVD was also increased in MUH-NW and MHO individuals (2.9 [1.3-6.4] and 3.9 [1.9-7.8], respectively). Results were consistent across gender and ethnic categories. CONCLUSION: The risk of developing DM and CVD is increased in MUH-NW and MHO individuals. Screening for obesity and other metabolic abnormalities should be routinely performed in clinical practice to institute appropriate preventive measures.