OBJECTIVE To report long-term outcomes of patients with stage II testicular seminoma treated with radiotherapy (RT). METHODS A retrospective review was performed of 52 patients who received megavoltage RT for stage II testicular seminoma at Mayo Clinic between 1974 and 2007. Forty-eight patients (92%) had computed tomography staging. Overall survival (OS), relapse-free survival (RFS), and cause-specific survival (CSS) were determined using the Kaplan-Meier method. Major cardiac event (MCE) was defined as myocardial infarction, coronary artery bypass grafting or stenting, or valve replacement. Second malignancy (SM) was defined as biopsy-confirmed malignancy occurring in the RT field. RESULTS The median patient age at diagnosis was 36 years. Stage was IIA (n = 24), IIB (n = 7), IIC (n = 17), and II not otherwise specified (NOS, n = 4). The median infradiaphragmatic RT dose was 30.7 Gy. Twenty-six patients (50%) received prophylactic mediastinal/supraclavicular (MSCV) RT. The median follow-up was 19 years. Estimates of OS, RFS, and CSS were 94%, 80%, and 96% at 10 years, and 83%, 72%, and 96% at 20 years, respectively. RFS at 10 years for stage IIA, IIB, IIC, and II NOS were 83%, 54%, 81%, and 100%, respectively (log-rank P = 0.21). Ten patients (19%) experienced disease relapse in the MSCV region (n = 7), para-aortic lymph nodes (n = 1), lung (n = 1), or peritoneal cavity (n = 1). Eight patients were successfully salvaged with chemotherapy and/or surgery, while 2 died of seminoma. Risk of MSCV relapse was significantly lower in patients who received MSCV RT vs. those who did not (10-year estimates: 4% vs. 21%, respectively, log-rank P = 0.01). MCE occurred in 10 patients (19%) at a median of 18 years (range 7-30) after RT. SM occurred in 5 patients (10%) at a median of 27 years (range 20-34) after RT. CONCLUSIONS In patients with stage II testicular seminoma treated with RT, relapse in the irradiated site was uncommon. Infradiaphragmatic RT alone was associated with a significant risk of MSCV failure. Most MCE and SM events occurred more than 20 years after RT, highlighting the importance of vigilant long-term follow-up.