Background: Nocturia (voids arising from sleep) is a ubiquitous phenomenon reflecting many diverse conditions but whether it has significance in its own right remains uncertain. We examined whether nocturia was an independent risk factor for mortality Methods: These were observational analyses employing primarily North American and European participants and included 7343 men, aged 50–75 years participating in the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial. Cox proportional hazards models were used to test the association between baseline nocturia (voiding ≥3 times per night) and all-cause mortality. Potential confounding variables included: age; race; region of origin; treatment group; self-reported coronary artery disease, diabetes mellitus, hypertension, and peripheral vascular disease; smoking; alcohol use; prostate volume; and diuretics. Self-reported sleep quality, as measured with the Medical Outcomes Study sleep scale, was entered as a final step in the model. Results: Nocturia was associated with increased mortality risk (hazard ratio [HR] = 1.72; 95% CI 1.15–2.55) independent from demographics and medical comorbidities. Inclusion of disturbed sleep in the model reduced the magnitude of the association (HR = 1.43; 95% CI 0.93–2.19). Conclusions: Although the findings are limited to men, half of whom ingested dutasteride, the interruption of sleep by nocturia may have long-term impact on health and may warrant targeted intervention.