We have examined the associations between dietary glycaemic index (GI), substitutions of total, low-, medium- and high-GI carbohydrates for fat and the risk of CHD. The study consisted of 21 955 male smokers, aged 50–69 years, within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The diet was assessed at baseline using a validated FFQ. During a 19-year follow-up, 4379 CHD cases (2377 non-fatal myocardial infarctions and 2002 CHD deaths) were identified from national registers. Relative risks (RR) and CI for CHD were analysed using Cox proportional hazards modelling, and multivariate nutrient density models were applied to examine the associations between the substitutions of macronutrients and the risk of CHD. Dietary GI was inversely associated with CHD risk: multivariate RR in the highest v. lowest quintile was 0·89 (95 % CI 0·81, 0·99). Replacement of higher-GI carbohydrates with lower-GI carbohydrates did not associate with the risk. Replacing saturated and trans-fatty acids with carbohydrates was associated with decreased CHD risk: RR for substitution of 2 % of energy intake was 0·97 (95 % CI 0·94, 0·99). On the contrary, replacing MUFA with carbohydrates was associated with an increased risk: RR for substitution of 2 % of energy intake was 1·08 (95 % CI 1·01, 1·16). We conclude that in the present study population, contrary to the hypothesis, a lower GI does not associate with a decreased risk of CHD. The associations of carbohydrates with CHD risk depend on the fatty acid composition of the diet.