Cross-sectional studies and animal experiments suggest that methylmercury exposure could increase the risk of hypertension. This relationship has not been evaluated in large prospective studies. Using data from previous nested case-control studies in 2 separate prospective cohorts, we measured toenail mercury, a valid biomarker of long-term methylmercury exposure, among 6045 US men and women free of hypertension at baseline. Geometric mean toenail mercury concentrations were 0.08 μg/g in the lowest quintile and 0.74 μg/g in the highest quintile, the latter corresponding with exposures ≈2.0-fold higher than the US Environmental Protection Agency reference dose. Participants were followed prospectively (mean±SD follow-up, 14.9±7.9 years) for a new self-report of physician-diagnosed hypertension (3540 cases), shown to be >95% sensitive and specific for diagnosing hypertension in these cohorts as compared with review of medical charts and direct blood pressure measurement, respectively. After adjustment for demographic, clinical, and lifestyle risk factors, the hazard ratio (95% CI) for incident hypertension in the highest versus lowest quintile of mercury exposure was 0.96 (0.84-1.09) in women, 0.82 (0.62-1.08) in men, and 0.94 (0.84-1.06) in both cohorts combined. Findings were similar when more extreme categories of mercury were compared (across deciles, with geometric mean levels in highest decile ≈2.9-fold higher than the reference dose) and in analyses stratified by fish or omega-3 consumption, selenium levels, body mass index, and age. These findings from 2 separate large prospective cohort studies do not support any clinically apparent adverse effects of methylmercury exposure on the risk of hypertension in men or women, including at levels ≤2.5-fold higher than the reference dose.