High density lipoproteins were measured on fasting blood samples from 4107 men and women. Control for reported alcohol consumption and subscapular skinfold thickness using multiple regression analysis allowed an examination of the relationship between cigarette smoking and HDL cholesterol. Cigarette smoking was found to be associated with an average difference in HDL cholesterol of about 4 mg/dl in men and 6 mg/dl in women. Furthermore, when heavy alcohol drinkers were eliminated a significant negative association between number of cigarettes smoked and HDL cholesterol was demonstrable in both men and women. There was no evidence that former cigarette smokers, with the exception of those who switched to cigars or pipes or had quit less than one year, had lower HDL levels. Cigar or pipe smokers who had never smoked cigarettes had alcohol- and skinfold-adjusted HDL cholesterol comparable to the non-smoker. These observations indicate another possible link between inhaled tobacco smoke and the atherosclerotic process and suggest the need for further studies and experiments that might clarify the mutual relationship of HDL cholesterol, cigarette smoking and the atherosclerotic process.