Abstract Purpose To determine the acute and late genitourinary (GU) and gastrointestinal (GI) toxicity and present short-term biochemical no evidence of disease (bNED) rates after high-dose-rate brachytherapy (HDR-B) monotherapy. Methods and Materials Between October 2003 and June 2006, 36 patients with low (28) and intermediate (8) risk prostate cancer (PCA) were treated by HDR-B monotherapy. All patients received one implant and four fractions of 9.5 Gy within 48 h for a total prescribed dose (PD) of 38 Gy. Five patients received hormonal therapy (HT). Median age was 63.5 years and median followup was 3 years (range, 0.4–4 years). Toxicity was scored according to the CTCAE version 3.0. Biochemical failure was defined according to the Phoenix criteria. Results Acute and late Grade 3 GU toxicity was observed in 1 (3%) and 4 (11%) patients, respectively. Grade 3 GI toxicity was absent. The three- year bNED survival rate was 100%. The sexual preservation rate in patients without HT was 75%. Late Grade 3 GU toxicity was associated with the planning target volume (PTV) V 100 (% PTV receiving ≥100% of the PD; p = 0.036), D 90 (dose delivered to 90% of the PTV; p = 0.02), and the urethral V 120 (urethral volume receiving ≥120% of the PD; p = 0.043). The urethral V 120 was associated with increased PTV V 100 ( p < 0.001) and D 90 ( p = 0.003). Conclusions After HDR-B monotherapy, late Grade 3 GU toxicity is associated with the urethral V 120 and the V 100 and D 90 of the PTV. Decrease of the irradiated urethral volume may reduce the GU toxicity and potentially improve the therapeutic ratio of this treatment.