Background: Although inflammation is involved in the development of atrial fibrillation (AF), the association of white blood cell (WBC) count and differential with AF has not been thoroughly examined in large cohorts with extended follow-up. Methods: We studied 14, 500 men and women (25% blacks, 55% women, mean age 54) free of AF at baseline (1987-89) from the Atherosclerosis Risk in Communities (ARIC) study, a community-based cohort in the United States. Incident AF cases through 2010 were identified from study electrocardiograms, hospital discharge records and death certificates. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for AF associated with WBC count and differential. Results: Over a median follow-up time of 21.5 years for the entire cohort, 1928 participants had incident AF. Higher total WBC count was associated with higher AF risk independent of AF risk factors and potential confounders (HR 1.09, 95% CI 1.04-1.15 per 1-standard deviation [SD] increase). Higher neutrophil and monocyte counts were positively associated with AF risk, while an inverse association was identified between lymphocyte count and AF (multivariable adjusted HRs 1.16, 95% CI 1.09-1.23; 1.05, 95% CI 1.00-1.11; 0.91, 95% CI 0.86-0.97 per 1-SD, respectively). No significant association was identified between eosinophils or basophils and AF. Conclusions: High total WBC, neutrophil, and monocyte counts were each associated with higher AF risk while lymphocyte count was inversely associated with AF risk. Systemic inflammation may underlie this association and requires further investigation for strategies to prevent AF.