Because alcohol consumption is associated with increased high density lipoprotein (HDL) cholesterol and decreased low density lipoprotein (LDL) cholesterol, and cigarette smoking is associated with lower HDL cholesterol and higher LDL cholesterol, there has been speculation that the protective effect of moderate alcohol consumption and/or the noxious effect of cigarette smoking for cardiovascular disease might be mediated in large part by a lipoprotein mechanism. The authors examined this question in a prospective study of 7,461 men and women in 10 North American populations initially seen in 1972-1976 and followed for an average of 8.5 years. Moderate alcohol consumption was weakly protective for cardiovascular disease, while cigarette smoking was strongly and significantly associated with cardiovascular disease mortality. As expected, LDL cholesterol was positively related and HDL cholesterol was inversely related to cardiovascular disease mortality. However, multivariable analysis of cardiovascular disease mortality alternately excluding and including HDL cholesterol and LDL cholesterol as covariates indicated that the effect of alcohol consumption on cardiovascular disease mortality was independent of an LDL cholesterol pathway and only partially mediated by an HDL cholesterol pathway, while the effect of cigarette smoking was independent of both the HDL cholesterol and LDL cholesterol pathways, suggesting alternative biologic mechanisms of action for both alcohol consumption and cigarette smoking on cardiovascular disease.