In non-diabetic subjects, the high-density lipoprotein (HDL) cholesterol level is increased by alcohol and decreased by smoking. The biallelic B1B2 polymorphism of the cholesteryl ester transfer protein (CETP) gene is a genetic determinant of HDL cholesterol. We evaluated the effect of moderate alcohol consumption, the CETP gene polymorphism and clinical variables on HDL cholesterol and other lipoprotein parameters in insulin-dependent diabetic (IDDM) men. Thirteen moderate alcohol using IDDM men (median alcohol consumption 17 g/d) and 13 abstainers, individually matched for the CETP gene polymorphism and clinical factors including smoking, were studied. HDL cholesterol, serum apo AI and serum CETP activity levels were very similar in alcohol users compared to abstainers (1.36 +/- 0.28 vs 1.36 +/- 0.36 mmol l-1, 1.71 +/- 0.31 vs 1.75 +/- 0.33 g l-1 and 134 +/- 27 vs 138 +/- 53 nmol l-1h-1, respectively, n.s. for all). No significant differences in apo B-containing lipoproteins were observed. Multiple regression analysis (multiple r = 0.68) showed that HDL cholesterol was positively associated with the presence of the B2 allele (0.23 mmol l-1 higher for each B2 allele present, p = 0.004) and negatively with smoking (0.15 mmol l-1 lower per 10 cigarettes smoked daily, p = 0.011), but not with alcohol consumption (p = 0.66). This study suggests that moderate alcohol consumption has no beneficial effect on the lipoprotein profile in IDDM men. HDL cholesterol is adversely influenced by smoking, whereas considerable variation in its level appears to be explained by the CETP gene polymorphism.