Background: Evidence supports the use of high dose-rate brachytherapy (HDR) as monotherapy for selected patients with low- and intermediate-risk prostate cancer when given in schedules of 4 or more fractions. There is limited data on the safety and efficacy of HDR given in fewer fractions. Our purpose is to report on acute toxicity (within 3 months) and early changes in health-related quality of life in a randomized trial comparing a single fraction and a 2-fraction protocol. Methods: A single center, randomized phase II clinical trial of HDR either as a single fraction of 19 Gy (1F), or as two fractions of 13.5 Gy (2F) given 1 week apart was undertaken between June 2013 and April 2015. Eligible patients had NCCN low- or intermediate-risk disease, a prostate volume < 60 cc, International Prostate Symptom Score (IPSS) of 18 or lower, no previous prostate surgery and no use of androgen deprivation therapy. Treatment was delivered using an out-patient ultrasound-based technique. Follow-up assessment was with CTCAE v4, IPSS and Expanded Prostate Composite Index (EPIC). Results: A total of 168 patients were randomized: 86 to 1F and 82 to 2F arms. Median age was 65 years, median prostate volume was 35 cc, and 91% had intermediate risk. Median follow-up was 12 months. Only 3 patients (1.8%) experienced acute grade 2 GI toxicity. The percentage of acute grade 2 GU toxicities is as follows: retention (48%), frequency (20%), urgency (4%). One patient experienced grade 3 hematuria. Ten patients (6%) had urinary retention but only 4 (2.5%) required use of a catheter for longer than 2 days. There was no difference in rate of grade 2 toxicity between treatment arms; the only factor associated with grade 2 urinary retention on univariate and multivariate analysis was prostate volume (p=0.0033). Mean EPIC urinary (p=0.0016) and sexual domain scores (p<0.0001) were lower at 6 months with no difference between treatment arms. Bowel and hormonal domain scores were unchanged. Conclusions: HDR 19 Gy x 1 or 13.5 Gy x 2 is very well tolerated acutely with no acute bowel toxicity. Mild to moderate acute urinary symptoms are common. No difference is found in acute toxicity or early health-related quality of life between treatments. Clinical trial information: NCT01890096