Unlike tobacco, the effect of marijuana smoke on subclinical atherosclerosis, a surrogate measure for cardiovascular disease, is not known. This study aimed to determine the association between lifetime exposure to marijuana and measures of subclinical atherosclerosis in mid-life. We used data from the US-based Coronary Artery Risk Development in Young Adults (CARDIA) study, a cohort of black and white men and women aged 18-30 years at baseline in 1985-86, with up to seven follow-up examinations over 25 years. A total of 3498 participants in the CARDIA study were included in this study. Cumulative years of exposure to marijuana (expressed in ‘marijuana-years’, with 1 marijuana-year equivalent to 365 days of use) using repeated assessments every 2-5 years for 25 years. Abdominal artery calcium (AAC) and coronary artery calcium (CAC) scores were measured by computed tomography at year 25 examination. Among 3117 participants with AAC and CAC measurements, 2627 (84%) reported past marijuana use and 1536 (49%) past daily tobacco smoking. Compared with tobacco smokers, 46% of whom reported 10 or more pack-years of use, only 12% of marijuana users reported 5 or more marijuana-years of use and only 6% reported having used marijuana daily. We found a significant interaction between never and ever tobacco users on the association between cumulative marijuana use and AAC (P = 0.05). Among those who never smoked tobacco, cumulative marijuana-years were not associated with AAC or CAC in models adjusted for demographics, cardiovascular risk factors, licit and illicit drug exposure and depression symptoms. However, among ever tobacco smokers, marijuana exposure was associated with AAC and CAC. At 5 marijuana-years of exposure, using AAC = 0 and CAC = 0 as a reference group, the odds ratio (OR) was 1.97 [95% confidence interval (CI) = 1.21-3.21, P = 0.007] for AAC > 0/CAC = 0 and 1.83 (95% CI = 1.02-3.31, P = 0.04) for CAC > 0), regardless of AAC. Tobacco smoking was associated strongly with both AAC and CAC. Marijuana use appears to be associated with subclinical atherosclerosis, but only among ever tobacco users.