Background and objective. A low activated protein C (APC) response increases the risk of venous thrombosis, and possibly arterial disease. Apart from the factor V Leiden mutation, other factors may determine the level of APC response. In most studies on the association with arterial disease, cardiovascular risk factors were not appropriately controlled for as possible confounders. We studied the association of APC response to cardiovascular risk factors in a sample of the general population. Methods. The Rotterdam Study is a cohort study among 7983 subjects aged 55 years or over, living in the Ommoord suburb in Rotterdam, The Netherlands. APC response was measured in 928 subjects as part of two case-control studies (subjects with and without symptomatic cardiovascular disease (CVD) and with and without dementia). APC response was determined in double centrifuged platelet poor plasma. Those on anticoagulants were excluded. Linear regression analyses were done in age strata (55-64, 65-74, 75-84, ≤ 85), with adjustment for age, sex, CVD, and dementia. Results. APC response was lower in women than in men (difference 0.56 (p < 0.01)). In men, APC response decreased with age (0.15 per decade (p = 0.02)). In women, a non-significant rise was seen (0.05 per decade (p = 0.27)). Associations with cardiovascular risk factors differed by age, not gender. In those aged 55-64 years inverse associations were found with total cholesterol (0.14 decrease per 1 mmol/l increase, p = 0.08) and diastolic pressure (0.12 decrease per 10 mmHg increase, p = 0.06). In those aged ≤ 85 years a positive association was seen with smoking (0.76 increase, p = 0.01). No associations were found with systolic pressure and body mass index. Conclusion. These findings suggest that in the elderly age, gender, serum lipids, diastolic pressure and smoking may influence APC response, the extent of which may differ by age. These factors should be allowed for in studies on the association between APC response and arterial disease.