Introduction and objectivesWe previously published the toxicity and initial results of a prospective cohort of patients treated with 2 fractions HDR-BRT administered in a single day. In the present analysis we report the long-term cancer control results of our prospective trial and investigate the relationship between PSA nadir and biochemical control. Material and methodsA total of 120 patients were treated with HDR Brachytherapy monotherapy administered in two fractions in a single day. Between November 2010 and February 2016, 84 patients with low-risk and 36 patients with intermediate-risk prostate cancer in accordance with the NCCN practice guidelines. ResultsMedian age was 66 years (range 45–84) and median PSA was 7.5 ng/ml (range 0.01–16 ng/ml). Overall, 84.2% had Gleason score 6 and 15.8% Gleason 7. Thirty-one percent of patients received ADT.After a median follow-up of the cohort was 123 months. Actuarial rates of no biochemical evidence of disease (bNED), overall survival, local control and metastasis-free survival for all patients were 93.3%, 86.7%, 95.2% and 96.1%, respectively.The median time to achieve PSA nadir was 80.5 months. Patients who attained a PSA Nadir ≤ 0.20 ng/mL exhibited a 10-year bNED survival rate of 96.9%, whereas thosewho failed to reach this PSA level had a survival rate of only 40%. ConclusionsIn patients with favorable localized prostate cancer, 2 fractions HDR-BT monotherapy is a highly curative radiation technique that attains PSA nadir levels < 0.2 ng/mL in 95% of cases.