Although C-reactive protein (CRP) is a major cardiovascular risk factor, its association with atrial fibrillation (AF) remains controversial. This study explored whether the CRP-related incidence of AF is modified by serum markers of inflammation in a population-based cohort with follow-up data. Serum CRP and 2 components of the complement system (C3 and C4) were determined in 1,011 healthy patients (25 to 64 years old). The incidence of AF was compared between groups defined by levels of CRP, C3, and C4. The follow-up time was 4 years. A high complement level was defined as either C3 or C4 in the top quartile. High CRP was associated with high complement components. An increased CRP level was associated with an increased incidence of AF. The complement components modified these associations. After risk factor adjustment, those with high CRP and high complement components had a significantly higher risk of AF (relative risk 3.0, 95% confidence interval 2.0 to 4.2) than those with normal CRP and low complement levels. In the absence of a high complement level, a high CRP level was not significantly associated with AF (relative risk 1.1, 95% confidence interval 1.0 to 1.4). In conclusion, high CRP levels are associated with high serum levels of complement components. These proteins increase the CRP-related incidence of AF. In the absence of elevated complement components, no statistically confirmed association was found between a high CRP level and AF.