Age and metabolic syndrome are major risk factors for atherosclerosis. However, limited information is available regarding whether cigarette smoking, another major, modifiable risk factor, has synergistic effects with age and metabolic syndrome on subclinical atherosclerosis, particularly in young adults. This aspect was examined in 1,051 adults (747 whites and 304 blacks; aged 24-43 years) from the Bogalusa Heart Study. General linear models were used to examine the effects of cigarette smoking and its interactive effects with age and metabolic syndrome on carotid intima-media thickness (CIMT). After adjusting for age, race, and sex, current smokers had lower BMI (mean ± SE: 27.4 ± 0.4, 29.3 ± 0.5, and 29.9 ± 0.3 kg/m2 in current, former, and never smokers, respectively; p<0.0001) and lower levels of fasting glucose (82.8 ± 0.9, 89.5 ± 2.3, and 87.1 ± 1.1 mg/dL, respectively; p = 0.001) and insulin (10.6 ± 0.4, 14.2 ± 1.0, 13.6 ± 0. 6 µU/ml, respectively; p<0.0001). Despite being lean and having favorable levels of glucose and insulin, current smokers had greater CIMT (0.850 ± 0.012, 0.808 ± 0.011, and 0.801 ± 0.006 mm, respectively; p = 0.0004). Importantly, cigarette smoking showed significant interactions with age and metabolic syndrome on CIMT: Age-related change in CIMT in current smokers was significantly greater (0.013 ± 0.002 mm/year) than in nonsmokers (former and never smokers combined) (0.008 ± 0.001 mm/year) (p for interaction = 0.005); the difference in CIMT between those with and without metabolic syndrome was significantly greater in current smokers (0.154 ± 0.030 mm, p<0.0001) than in nonsmokers (0.031 ± 0.014 mm, p = 0.03) (p for interaction<0.0001). In conclusion, cigarette smoking significantly exacerbates the adverse effects of age and metabolic syndrome on subclinical atherosclerosis in young adults, which underscores the importance of prevention and cessation of cigarette smoking behavior in the young.