Individual plasma carotenoids have been associated with various chronic diseases but little is known about the relationship between total plasma carotenoids and risk factors for chronic diseases. In the Physicians' Health Study, we examined 492 men free of CVD and cancer for the relationship between total plasma carotenoids (the sum of alpha-carotene, beta-carotene, lycopene, zeaxanthin, lutein and beta-cryptoxanthin) and a wide variety of factors that predict chronic disease. Multivariate linear and logistic regression was performed to calculate parameter estimates (95% CI) and OR (95% CI) for total plasma carotenoids. In linear regression models, BMI, hypertension, alcohol intake and plasma levels of each lipid parameter and a-tocopherol significantly predicted levels of total plasma carotenoids. Upon adjustment for multiple chronic disease risk factors, the OR for levels of total plasma carotenoids greater than or equal to the median (> or=1.301 micromol/l) was statistically significant for current smoking (OR 0.21; 95% CI 0.06, 0.77), weekly alcohol ingestion (OR 2.30; 95% CI 1.06, 4.99), daily alcohol ingestion (OR 2.46; 95% CI 1.29, 4.67), each 100 mg/l increase in total cholesterol (OR 0.73; 95% CI 0.58, 0.91), LDL-cholesterol (OR 1.48; 95% CI 1.17, 1.89) and HDL-cholesterol (OR 1.58; 95% CI 1.26, 1.99), each 100 mg/ml increase in intercellular adhesion molecule-1 (OR 0.70; 95% CI 0.53, 0.93) and each 10 micromol/l increase in alpha-tocopherol (OR 1.33; 95% CI 1.12, 1.57), using logistic regression. Few lifestyle and clinical risk factors appear to be related to levels of total plasma carotenoids; however, levels of biomarkers such as plasma lipids and alpha-tocopherol may be strongly related.