OBJECTIVES: This study aimed to investigate the interaction between a genetic risk score for coronary artery disease (CAD) and measures of physical activity on coronary artery calcification (CAC) in a population-based cohort. Specifically, it sought to determine whether physical exercise, known to be protective against high CAC, influences the expression of genetic risk factors for CAD. METHODS: Data were obtained from the Heinz Nixdorf Recall study, including 3938 participants aged 45-74 years with European ancestry. CAC was measured using electron beam computed tomography. The genetic risk score (GRSCAD) was calculated using 158 CAD-related genetic loci. Physical activity during the last four weeks was assessed through standardized interviews, resulting in measures of (1) engagement in physical exercise and (2) the total metabolic equivalents of general physical activity per week (METh/week). Linear regression models were used to analyze the associations of physical activity and genetic risk with log-transformed CAC, adjusting for confounders age, sex, and education. RESULTS: Participants not engaging in physical exercise had a 1.336-fold (95%-CI: 1.171 to 1.533) higher CAC compared to those who exercised. No association was found between METh/week and CAC. The GRSCAD was associated with a 1.206-fold (95%-CI: 1.130 to 1.287) higher CAC per standard deviation. Interaction analyses indicated that the genetic effect on CAC was slightly stronger in participants with higher METh/week levels, showing a 1.306-fold (95%-CI: 1.145 to 1.490) higher CAC per standard deviation of the GRSCAD in the highest METh/week quartile compared to 1.109-fold (95%-CI: 0.978 to 1.259) higher CAC in the lowest quartile. No interaction was observed for engagement in physical exercise. CONCLUSIONS: While physical activity in sum was associated with lower levels of CAC, individuals reporting higher physical activity levels may also be less exposed to other non-genetic risk factors for CAD, leading to a slightly stronger association of genetic factors with CAC.