OBJECTIVES/SPECIFIC AIMS: This study applied a syndemic framework to 1) assess whether the concurrence of unhealthy alcohol use, smoking, and depressive symptoms is associated with increased risk for incident CVD among people living with and without HIV and 2) determine whether the association between this syndemic and incident CVD is differential by HIV status. METHODS/STUDY POPULATION: We evaluated 5731 participants (50.3% HIV+) without baseline CVD from the Veterans Aging Cohort Study, a prospective, observational cohort of PLWH and matched uninfected veterans enrolled in 2002 and followed through 2015. We assessed baseline number of conditions (syndemic score: 0-3; unhealthy alcohol use (>14 drinks per week for men [women] or 5 or more drinks in one occasion for men [women]), cigarette smoking (former/current), and depressive symptoms (Patient Health Questionnaire-9 score ≥ 10) and incident CVD through 14 years. Clinical ICD-9 codes identified incident cases of CVD (acute myocardial infarction, heart failure, revascularization, and stroke). We constructed age-adjusted survival curves and CVD rates. Multivariable Cox proportional hazards regressions estimated the hazard ratio (HR) and 95% confidence intervals (CI) of the syndemic score on incident CVD by HIV status, adjusting for baseline demographic, health status, and HIV-related factors. RESULTS/ANTICIPATED RESULTS: Under 10% of all veterans had zero conditions; 25.8% had one; 49.6% had two, and 14.3% had all three. Based on the prevalence of each individual condition in the cohort (unhealthy drinking: 41.5%, cigarette smoking: 75.0%, and depressive symptoms: 21.3%), the observed prevalence of all three conditions was more than double that expected by chance (6.6%). There were 835 cases of incident CVD (50.4% HIV+) during the median follow-up (10.6 years). Overall, age-adjusted incidence rates/1000 person-years increased with greater number of conditions (zero 10.1, one 12.5, two 15.8, three 19.6). Compared to uninfected people with zero conditions, the adjusted hazard ratios of incident CVD were similar by HIV status for each number of conditions. DISCUSSION/SIGNIFICANCE OF IMPACT: The syndemic of unhealthy drinking, cigarette smoking, and depressive symptoms is common and associated with high CVD risk. However, this risk was similar by HIV status. Our results underscore the need to screen for and treat these co-occurring conditions.