Background: TCS are at increased risk of CVD. Few clinical studies have comprehensively evaluated CVD risk factors through physical exams, lipid panels, and health behaviors in North American TCS. Methods: Eligible TCS were < 50 y at diagnosis and treated with only first line CHEM. TCS underwent physical exams, had fasting lipid panels, and completed questionnaires regarding comorbidities and health behaviors. Age, race, and educational status-matched controls (1:1) were chosen from the general population using the 2011-2012 National Health and Nutrition Examination Survey. Odds ratios (OR) of outcomes among TCS vs. controls were estimated using logistic regression models. Results: We evaluated the first 680 enrolled TCS (fasting = 114). Median age at diagnosis was 31 y (range, 15-49) and at clinical evaluation 39 y (range, 19-68). Median time since CHEM was 4 y (range, 1-30). Compared to normative controls, TCS were more likely to be overweight (OR = 1.65; 95% CI 1.26-2.16), have total cholesterol ≥ 240 mg/dL (OR = 2.47; 95% CI 1.29-4.70) and LDL ≥ 160 mg/dL (OR = 3.39; 95% CI 1.18-9.73), and report alcohol use > 2 days/week (OR = 2.12; 95% CI 1.63-2.76). In contrast, they were less likely to have a waist circumference > 40 inches (OR = 0.75; 95% CI 0.59-0.95) or currently smoke (OR = 0.32; 95% CI 0.23-0.45); and more likely to engage in vigorous (OR = 4.21; 95% CI 3.36-5.29) or moderate (OR = 17.0; 95% CI 11.5-24.9) physical activity. TCS were about 3 times more likely to report excellent, very good, or good health compared to controls (P < 0.05). No significant differences were seen comparing HDL, triglycerides, or self-reported hypertension (P > 0.05). Conclusions: Although North American TCS appear more likely to exercise and abstain from smoking compared to normative controls, a greater proportion are overweight and have higher fasting total cholesterol and LDL levels. Health care providers should screen TCS for CVD risk factors, and encourage practices consistent with a healthy lifestyle. Future research should elucidate mechanisms of increased CVD risk and ultimately develop customized prevention and intervention strategies.