Introduction: Chronic scrotal pain is difficult to manage, and epididymectomy is a treatment option for a subset of men with pain localized to the epididymis. We sought to evaluate the efficacy of epididymectomy at our institution. Methods: Between 2000 and 2020, 225 men underwent epididymectomy at our institution for pain localized to the epididymis and not part of a greater constellation of pelvic pain or urinary symptoms. Our primary outcome measure was change in pain after epididymectomy, categorized as cured/improved or no change/worsened. Multivariable logistic regression compared the impact of pain duration, and surgical and psychiatric histories on postoperative pain. Results: Patients in both outcome categories-cured/improved and no change/worsened-were similar in age and BMI. Overall, 162 patients (72%) reported cured/improved pain at the last documented follow-up visit. Median follow-up time was 12 (IQR 1-364) weeks. About half of the cohort (n = 117, 52%) had a prior vasectomy, and there was no difference in outcome based on vasectomy history on multivariate analysis (OR 0.625, P = .3). Men with pain duration > 1 year (OR 0.46, P = .03), diagnosed psychiatric conditions (OR 0.44, P = .04), or prior scrotal/inguinal/abdominal surgeries other than vasectomy (OR 0.47, P = .03) had decreased odds of pain relief after epididymectomy. Conclusions: This 20-year analysis is the largest review of postepididymectomy outcomes reported. Among carefully screened men, 72% had resolution or improvement of scrotal pain. Epididymectomy is most effective for men with < 1 year of focal epididymal pain, with no history of psychiatric conditions or scrotal/inguinal/abdominal surgery other than vasectomy.