The presence of systemic inflammation determined by elevations in high-sensitivity C-reactive protein (hs-CRP) has been associated with persistence of atrial fibrillation (AF). The influence of inflammation markers, such as hs-CRP, on the recurrences of lone AF, however, has not been clarified. We tested the hypothesis of whether, in patients with a first paroxysmal episode of lone AF, the hs-CRP levels were elevated, and whether elevated hs-CRP could predict the recurrence rate of lone AF in patients without antiarrhythmic drugs. Using a case-control study design, the hs-CRP levels in 125 patients with a documented symptomatic first paroxysmal episode of lone AF was compared with the hs-CRP levels in 65 control patients. hs-CRP levels are presented as median values with the interquartile range (25th to 75th percentiles). The hazard ratio compared the 75th percentile of hs-CRP with the 25th percentile. In the arrhythmia group, hs-CRP was higher than in the control patients (median 0.23 mg/dl, interquartile range 0.12 to 0.49, vs 0.087 mg/dl, interquartile range 0.058 to 0.098, p <0.001). After adjusting for baseline characteristics, including, age, gender, and baseline blood pressure, hs-CRP remained a significant predictor of recurrent AF (hazard ratio 1.15, 95% confidence interval 1.04 to 1.24, p = 0.002) at 2 years of follow-up. In conclusion, this study is the first to document that the first paroxysmal episode of lone AF is associated with elevated hs-CRP levels, suggesting that hs-CRP may be a marker for inflammatory states that may promote the initiation of lone AF. These pathways may represent a novel mechanism by which structural changes resulting from inflammation could induce lone AF. The elevated hs-CRP levels could also predict the recurrence rate of lone AF in patients without antiarrhythmic drugs.