We investigated the interaction between genetic and environmental factors in the regulation of plasma HDL cholesterol concentration by determining TaqI and EcoN I restriction fragment length polymorphisms at the cholesteryl ester transfer protein (CETP) gene locus in 93 male alcohol drinkers and 82 control men. The highest plasma CETP activity and the lowest HDL cholesterol concentration were in the control subjects who were homozygous for the presence of the TaqI B restriction site (genotype 1-1). The lowest CETP activity and the highest HDL cholesterol among the control subjects were in those with genotype 2-2. These associations were, however, evident only in the non-smokers (P = 0.03 for CETP activity and P = 0.05 for HDL cholesterol). The non-smoking control subjects with genotype 1-1 had 19% higher CETP activity and 16% lower HDL cholesterol than those with genotype 2-2 (mean +/- S.D., 113 +/- 25 nmol/h/ml and 1.16 +/- 0.30 mmol/l vs. 95 +/- 16 nmol/h/ml and 1.38 +/- 0.34 mmol/l, respectively), and CETP activity and HDL cholesterol were negatively correlated (r = -0.280, P = 0.03, n = 59). The alcohol drinkers had 30% lower CETP activity (P < 0.001) and 48% higher HDL cholesterol (P < 0.001) than the controls. CETP activity was not affected by the TaqI B genotype in the alcohol drinkers. The lowest HDL cholesterol was in subjects with genotype 1-1 (1.68 +/- 0.60 mmol/l), but those with genotype 2-2 had lower HDL cholesterol than those with genotype 1-2 (1.78 +/- 0.59 and 1.93 +/- 0.66 mmol/l, respectively). The data of the alcohol drinkers fitted better with the quadratic regression model than with the linear one, suggesting a trend towards a curved relationship between the TaqI B genotype and HDL cholesterol in both the non-smoking and smoking alcohol drinkers. Total, LDL or VLDL cholesterol, total or VLDL triglycerides did not differ between the TaqI B genotypes either in the alcohol drinkers or the controls. Lipid and lipoprotein levels and CETP activities were likewise similar in the TaqI A and EcoN I polymorphisms. Our data indicate that CETP TaqI B polymorphism is related to plasma CETP activity and HDL cholesterol concentration in non-smoking men, but these associations are affected by smoking and alcohol drinking.