Very long-term mortality in men with early prostate cancer treated with surgery versus observation is uncertain. To determine long-term effects of surgery versus observation on all-cause mortality for men with early prostate cancer. This study evaluated long-term follow-up of a randomized trial conducted at the US Department of Veterans Affairs and National Cancer Institute sites. The participants were men (n = 731) ≤75 yr of age with localized prostate cancer, prostate-specific antigen (PSA) <50 ng/ml, life expectancy ≥10 yr, and medically fit for surgery. Radical prostatectomy versus observation. All-cause mortality was assessed in the entire cohort and patient and tumor subgroups. Intention-to-treat analysis was conducted using Kaplan-Meier methods with log-rank tests and Cox proportional hazard models; cumulative mortality incidence, between-group differences, and relative risks were also assessed at predefined time periods. During 22.1 yr (median follow-up for survivors = 18.6 yr; interquartile range: 16.6–20.0), 515 men died; 246 of 346 men (68%) were assigned to surgery versus 269 of 367 (73%) assigned to observation (hazard ratio 0.84 [95% confidence interval {CI}: 0.70–1.00]; p = 0.044 [absolute risk reduction = 5.7 percentage points, 95% CI: –0.89 to 12%]; relative risk: 0.92 [95% CI: 0.84–1.01]). The restricted mean survival in the surgical group was 13.6 yr (95% CI: 12.9–14.3) versus 12.6 yr (95% CI: 11.8–13.3) in the observation group; a mean of 1 life-year was gained with surgery. Results did not significantly vary by patient or tumor characteristics, although differences were larger favoring surgery among men aged <65 yr, of white race, and having better health status, fewer comorbidities, ≥34% positive prostate biopsy cores, and intermediate-risk disease. Results were not adjusted for multiple comparisons, and we could not assess outcomes other than all-cause mortality. Surgery was associated with small very long-term reductions in all-cause mortality and increases in years of life gained. Absolute effects did not vary markedly by patient characteristics. Absolute effects and mean survival were much smaller in men with low-risk disease, but were greater in men with intermediate-risk disease although not in men with high-risk disease. In this randomized study, we evaluated death from any cause in men with early prostate cancer treated with either surgery or observation. Overall, surgery may provide small very long-term reductions in death from any cause and increases in years of life gained. Absolute effects were much smaller in men with low-risk disease, but were greater in men with intermediate-risk disease although not in men with high-risk disease. Strategies are needed to identify men needing and benefitting from surgery while reducing ineffective treatment and overtreatment. Surgery may be associated with small reductions in all-cause mortality compared with observation in men with early prostate cancer. Strategies are needed to communicate these findings, enhance identification of individuals benefitting from early intervention, and reduce ineffective and/or overtreatment harms. [ABSTRACT FROM AUTHOR]