Purpose There are no randomized trials to guide treatment decisions between radiotherapeutic and surgical options for patients with high-risk localized prostate cancer. Comparative studies have been limited by their ability to match patients on the basis of pretreatment prognostic variables and to adjust for the cancer-related, medical, and socioeconomic differences between patients who choose radiotherapeutic or surgical approaches. Methods We analyzed the outcome of all patients in the National Cancer Database with high-risk, clinically localized prostate cancer with complete prognostic data who were treated with either radical prostatectomy (RP), external beam radiotherapy (EBRT) combined with androgen deprivation (AD), or EBRT plus brachytherapy with or without AD. Inverse probability of treatment weighting was used to adjust for covariable imbalance among treatment groups. The weighted time-dependent Cox proportional hazards model was then used to estimate the effects of treatment groups on survival, accounting for differential treatment initiation times. A predictive model of pathologic nodal (pLN) status was built using prostate-specific antigen level, Gleason score, and clinical T stage; predicted pLN status was used to repeat the inverse probability of treatment weighting and time-dependent Cox proportional hazards model. Results A total of 42,765 patients were analyzed. There was no statistically significant difference in survival between RP and EBRT plus brachytherapy with or without AD (hazard ratio [HR], 1.17; 95% CI, 0.88 to 1.55). However, EBRT plus AD was associated with higher mortality than RP (HR, 1.53; 95% CI, 1.22 to 1.92). Adjustment for predicted pLN status did not yield statistically different results. A sensitivity analysis showed that EBRT plus AD ≥ 7920 cGy narrowed the difference, but a significantly higher mortality remained (HR, 1.33; 95% CI, 1.05 to 1.68). Conclusion After comprehensively adjusting for imbalances in prostate cancer prognostic factors, other medical conditions, and socioeconomic factors, this analysis showed no statistical difference in survival between patients treated with RP versus EBRT plus brachytherapy with or without AD. EBRT plus AD was associated with lower survival.