Abstract Background MicroRNA (miRNA) expression in atrial tissue has been implicated in pathologic susceptibility to atrial fibrillation (AF). Nevertheless, data are limited on how circulating levels relate to AF. Objective To test the hypothesis that circulating miRNAs would be associated with AF. Methods Among 2445 Framingham Heart Study Offspring participants, we measured the expression of 385 circulating whole blood miRNAs by high-throughput quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). We related miRNA levels with prevalent and new-onset AF. Results The mean age in the cohort was 66.3 ± 8.9 years and 56% were women; 153 participants had clinically apparent AF at baseline and 107 developed AF during a median of 5.4 years of follow-up. miRNA-328 (miR-328) expression was lower among participants with prevalent AF [7.75 cycle threshold (Ct)] compared to individuals with no AF (8.76 Ct, p <0.001). The association between miR-328 and prevalent AF persisted after adjustment for age, sex, and technical covariates (OR=1.21, P = 1.8 x 10-4) but was attenuated in analyses adjusting for clinical AF risk factors (OR=1.14, P = 0.017). In contrast to the associations between miR-328 and prevalent AF, none of the circulating miRNAs were associated with incident AF. Conclusions Circulating levels of miR-328, a miRNA known to promote atrial electrical remodeling by reducing L-type Ca2+ channel density, were associated with prevalent AF. Adjustment for risk factors that promote atrial remodeling, including hypertension, attenuated the association between miR-328 and AF, potentially implicating miR-328 as a potential mediator of atrial remodeling and AF vulnerability.