Purpose: To compare rectal toxicity, urinary toxicity, and nadir+2 PSA relapse-free survival (bRFS) in two consecutive Phase II protocols of high-dose-rate (HDR) brachytherapy used at the authors institution from 2001 to 2012. Methods and Materials: Patients with National Comprehensive Cancer Network high risk and very high risk prostate cancer enrolled in studies HDR4 (2001-2007, n = 183) and HDR2 (2007-2012, n = 56) were analyzed. Patients received minipelvis external beam radiation therapy/intensity-modulated external radiotherapy to 54 Gy and 2 years of androgen blockade along with HDR brachytherapy. HDR4 protocol consisted of four 4.75 Gy fractions delivered in 48 hours; the HDR2 protocol delivered two 9.5 Gy fractions in 24 hours. Average 2-Gy equivalent dose (¿/ß = 1.2) prostate D90 doses for the HDR4 and HDR2 groups were 89.8 Gy and 110.5 Gy, respectively (p = 0.0001). Both groups were well balanced regarding risk factors. Prior transurethral resection of the prostate was more frequent in the HDR2 group (p = 0.001). Results: After a median followup of 7.4 years (range, 2-11.2), there was no difference in adverse grade ¿ 2 rectal events (HDR4 = 10.4% vs. HDR2 = 12.5%; p = ns) or grade ¿3 (HDR4 = 2.2% vs. HDR2 = 3.6%; p = ns). No differences in urinary grade ¿2 adverse events (HDR4 = 23% vs. HDR2 = 26.8%; p = ns) or grade ¿3 (HDR4 = 7.7% vs. HDR2 = 8.9%; p = ns) were detected. The 7-year bRFS for HDR4 and HDR2 protocols was 88.7% and 87.8%, respectively (p = ns). Conclusions: HDR4 and HDR2 protocols produce similar results in terms of toxicity and bRFS at the intermediate time point of 7 years.