Recent studies have implicated systemic inflammation in the genesis and maintenance of atrial fibrillation (AF). A robust inflammatory response is an integral component of the response to tissue injury during acute myocardial infarction (AMI). However, there is no information concerning the association between inflammation and AF in patients with AMI. We studied 1,209 patients admitted for AMI. C-reactive protein (CRP) was measured by a high-sensitivity assay within 12 to 24 hours after symptom onset. The relation between CRP and new-onset AF occurring during the hospital course and at 1 year was analyzed using multivariable logistic regression and Cox models, respectively. New-onset AF during hospitalization occurred in 6.5%, 10.4%, and 17.1% of patients in the first, second and third CRP tertiles, respectively (p trend <0.0001). In a multivariable logistic regression, adjusting for clinical variables and ejection fraction, compared with patients in the first CRP tertile, the odds ratios for AF were 1.5 (95% confidence interval 0.9 to 2.5, p = 0.15) and 2.0 (95% confidence interval 1.2 to 3.3, p = 0.008) in patients in the second and third CRP tertiles, respectively (p for trend = 0.007). In a Cox multivariate analysis, CRP remained an independent predictor of new-onset AF at 1 year. In conclusion, in a large cohort of patients with AMI, there was a graded positive association between increased CRP and new-onset AF. Inflammation may contribute to the development of AF in the setting of AMI.