Sex differences in cardiovascular risk factors, cardiac structure and function, and disease and symptom burden in the common arrhythmia atrial fibrillation (AF) have not been investigated systematically at the population level. Cross-sectional data of 14,796 subjects (age range 35 to 74 years, 50.5% men) from the population-based Gutenberg Health Study were examined to show the distribution of cardiovascular risk factors by AF status and sex, and to determine sex-specific predictors for AF. The prevalence of AF was higher in men (4.3%) than in women (1.9%). Men had a worse cardiovascular risk factor profile, a higher prevalence of cardiovascular disease, but fewer symptoms than women. Age-adjusted Cox regressions showed sex interactions in the association of high-density lipoprotein-cholesterol, triglycerides, diabetes mellitus, coronary artery disease, myocardial infarction, generalized anxiety disorder, and heart rate with AF. After multivariable adjustment, sex interactions were seen for thickness of interventricular end-diastolic septum, odds ratio (OR) per standard deviation (SD), 95% confidence interval women: 0.9 (0.8, 1.1), men: 1.2 (1.1, 1.4), interaction p value = 0.02; left atrial diameter index, OR per SD women: 1.5 (1.3, 1.8), men: 1.9 (1.7, 2.1), interaction p value = 0.03; and myocardial infarction, OR women: 2.7 (1.3, 5.6), men: 0.7 (0.5, 1.1), interaction p value = 0.002. In conclusion, in our large cohort, we observed substantial sex differences in AF distribution and clinical characteristics including comorbidities, symptom burden, and structural cardiac changes.