OBJECTIVES: Higher body mass index (BMI) is an important risk factor for atrial fibrillation (AF). The adipokines leptin, adiponectin and resistin are correlates of BMI, but their association with incident AF is not well known. We explored this relationship in a large cohort of postmenopausal women. METHODS: We studied an ethnically diverse cohort of community-dwelling postmenopausal women aged 50-79 who were nationally recruited at 40 clinical centres as part of the Women's Health Initiative investigation. Participants underwent measurements of baseline serum leptin, adiponectin and resistin levels and were followed for incident AF. Adipokine levels were log transformed and normalised using inverse probability weighting. Cox proportional hazard regression models were used to estimate associations with adjustment for known AF risk factors. RESULTS: Of the 4937 participants included, 892 developed AF over a follow-up of 11.1 years. Those with AF had higher mean leptin (14.9 pg/mL vs 13.9 pg/mL), adiponectin (26.3 ug/mL vs 24.5 ug/mL) and resistin (12.9 ng/mL vs 12.1 ng/mL) levels. After multivariable adjustment, neither log leptin nor log adiponectin levels were significantly associated with incident AF. However, log resistin levels remained significantly associated with incident AF (HR=1.57 per 1 log (ng/mL) increase, p=0.006). Additional adjustment for inflammatory cytokines only partially attenuated the association between resistin and incident AF (HR=1.43, p=0.06 adjusting for C-reactive protein (CRP); HR=1.39, p=0.08 adjusting for IL-6). Adjusting for resistin partially attenuated the association between BMI and incident AF (HR=1.14 per 5 kg/m(2), p=0.006 without resistin; HR=1.12, p=0.02 with resistin). CONCLUSIONS: In women, elevated levels of serum resistin are significantly associated with higher rates of incident AF and partially mediate the association between BMI and AF. In the same population, leptin and adiponectin levels are not significantly associated with AF.