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Racial minorities are at greater risk of cardiovascular disease (CVD), and CVD is the primary cause of mortality among human immunodeficiency virus (HIV)–infected individuals. Cocaine use also has been associated with hypertension. This study examined the contribution of lifestyle factors to systolic, diastolic, and mean arterial pressure (MAP) among people living with HIV and cocaine users from racially and ethnically diverse backgrounds.Participants (N = 401: 213 men, 188 women) aged 18 to 50 years with no history of CVD were recruited from South Florida. A total of 200 participants were HIV-cocaine-infected, 100 were HIV-infected individuals with no history of cocaine use, and 101 were HIV-uninfected individuals with cocaine abuse or dependence. Carotid intima-media thickness and plaque, blood pressure (BP), and lifestyle risk were assessed.Mean age was 36 years (standard deviation 9.33); the majority (62%) were African American. Carotid plaques were identified in 23% of participants; 42% were obese, 68% engaged in ≥150 minutes of weekly exercise, and 68% were smokers. Sex, body mass index (BMI), and diet were associated with systolic BP. Age, BMI, cannabis use, and diet were associated with diastolic BP and MAP.Age, BMI, cannabis use, and diet were associated with increased diastolic BP and MAP. Cocaine did not emerge as a significant predictor of CVD after controlling for cannabis dependence. Cocaine and HIV lacked significant association with CVD, possibly because the majority of the sample was younger than age 40. Lifestyle modifications and substance abuse counseling may be important in preventing CVD among those without a history of CVD.