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Prospective studies have shown that social isolation (i.e. lack of social contacts) predicts incident coronary heart disease (CHD), but it is unclear whether it predicts incident heart failure (HF) and what factors might mediate this association. HF patients may be more susceptible to social isolation as they tend to be older and may have disrupted social relationships due to life course factors (e.g. retirement or bereavement). We prospectively examined whether individuals with higher vs. low social isolation have a higher incidence of HF and determined whether this association is mediated by vital exhaustion.We estimated incident HF hospitalization or death among 14 348 participants from Visit 2 (1990–1992) in the Atherosclerosis Risk in Communities (ARIC) study using Cox proportional hazard models which were sequentially adjusted for age, race/study community, gender, current smoking, alcohol use, and co-morbidities. We conducted mediation analyses according to the Baron and Kenny method. After a median follow-up of 16.9 person-years, 1727 (13.0%) incident HF events occurred. The adjusted hazard of incident HF was greater for those in the higher vs. low social isolation risk group (hazard ratio 1.21, 95% confidence interval 1.08–1.35). Our data suggest that vital exhaustion strongly mediates the association between higher social isolation and incident HF (the percentage change in beta coefficient for higher vs. low social isolation groups after adjusting for vital exhaustion was 36%).These data suggest that greater social isolation is an independent risk factor for incident HF, and this association appears to be strongly mediated by vital exhaustion.