Background & aims: Dietary intake of several specific macronutrients has been linked to risk of coronary heart disease (CHD). However, these associations may depend on overall macronutrient composition rather than effects of one single macronutrient. Therefore, we aimed to investigate the associations of macronutrient intake and CHD and its related risk factors, by taking into account different macronutrient substitutions. Methods: This study was performed among 5873 participants from the Rotterdam Study, a population-based cohort study. Macronutrient intake was measured using a semi-quantitative food-frequency questionnaire. Cox proportional hazard regression analyses were used to examine associations between intakes of macronutrients and CHD incidence; and linear regression analyses were used to examine associations with the related risk factors, including triglycerides, total, high-density and low-density cholesterol levels, body mass index (BMI), fat mass index (FMI), and fat-free mass index (FFMI). Results: We documented 669 CHD cases during 74,776 person-years of follow-up. In multivariable-adjusted models we observed no statistically significant associations between macronutrients and CHD incidence. Although non-significant, a higher plant protein intake tended to be associated with a lower risk of CHD when consumed at the expense of any of the other macronutrients. This association was strongest when 5% of energy (5 E%) of plant protein was consumed at the expense of animal protein (HR = 0.61; 95% CI 0.31, 1,21), mono- and disaccharides (HR = 0.62; 95% CI 0.29, 1.35) or saturated fat (HR = 0.61; 95% CI 0.31, 1.20). No consistent associations were observed for risk factors related to CHD. Conclusions: Macronutrient composition was not significantly associated with CHD incidence or cardiometabolic risk factors in an adult population. Future studies should further investigate food sources and quality of macronutrients.