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Simple Summary: Stereotactic body radiotherapy (SBRT) is a contemporary treatment option for prostate cancer with excellent efficacy and low toxicity. Traditionally, this treatment option was used for patients with low- to intermediate-risk prostate cancer but there is emerging data for the high-risk setting. However, the optimal fractionation schedule for prostate SBRT remains an interesting research question. We therefore compared two cohorts that received radiotherapy with different treatment schedules regarding efficacy and toxicity. These patients included in these cohort were specifically matched, so that they would be similar. Purpose: To compare two stereotactic body radiotherapy (SBRT) regimens in patients with intermediate- or high-risk prostate cancer with regards toxicity and efficacy. Methods/Material: We retrospectively collected data from 198 patients treated with SBRT for prostate cancer at two different institutions. Patients received either 35–36.25 Gy in five fractions (group A) using Cyberknife robotic platform or 42.7 Gy in seven fractions (group B) using a C-arm LINAC (image-guided). Propensity score matching was done (2:1 nearest neighbor matching without replacement), resulting in 120 patients (80 patients for group A, 40 patients for group B). Toxicity, PSA nadir, biochemical failure and disease-free survival (DFS) were analyzed. Results: Median follow up of all patients was 13 months (range 1–91 months). Overall, 23.3% of patients had ≥G2 acute GU toxicity (21.1% group A versus 30% group B (p = 0.222)) and 6.6% of patients ≥G2 GI toxicity (2.5% versus 15% (p = 0.010)). There was one acute G3 GU toxicity in arm A and one acute G4 rectal bleeding in group B (anticoagulated patient). Regarding late toxicity, 14.1% of patients had ≥G2 late GU toxicity (17.4% versus 6.6% (p = 0.159)) and 5.0% of patients had ≥G2 late GI toxicity (1.4% versus 13.3% (p = 0.013)). There was one G3 late GU toxicity in arm B and two G3 late GI toxicities, one in each arm. Relative median PSA reduction was 92.4% (−53.9–99.9%) from baseline PSA (93.7% (−53.9–99.9%) in group A versus 87.7% (39.8–99.9%) in group B (p = 0.043). In total, 4.2% of patients had biochemical relapse, 5.0% in group A and 2.5% in group B (p = 0.518). One-year DFS in the overall cohort was 97.3%, 98.8% in group A and 94.3% in group B (p = 0.318). Conclusion: Both SBRT regimens have acceptable acute and late toxicity and good efficacy. There are significantly more GI toxicities in the seven-fraction regimen. Longer follow-up is warranted for better comparison of long-term efficacy. [ABSTRACT FROM AUTHOR]