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Purpose One of the characteristics of Prostate-Specific Antigen (PSA) is PSA slope. It is the rate of diminishing PSA marker over time after radiotherapy (RT) in prostate cancer (PC) patients. The purpose of this study was to evaluate the relationship between increasing RT doses and PSA slope as a potential surrogate for PC recurrence. Patients and Methods This retrospective study was conducted on PC patients who were treated by radiotherapy in the Cancer Institute of Iran during 2007–2012. By reviewing the records of these patients, the baseline PSA measurement before treatment (iPSA), Gleason score (GS), clinical T stage (T. stage), and periodic PSA measurements after RT and the total radiation dose received were extracted for each patient separately. We used a Bayesian dose-response model, analysis of variance, Kruskal–Wallis test, Kaplan–Meier product-limit method for analysis. Probability values less 0.05 were considered statistically significant. Results Based on the D’Amico risk assessment system, 13.34% of patients were classified as “Low Risk”, 51.79% were “Intermediate Risk”, and 34.87% were “High Risk”. In terms of radiation doses, 12.31% of the patients received fewer than 50 Gy, 15.38% received 50 to 69 Gy, 61.03% received 70 Gy, and 11.28% received more than 70 Gy. The PSA values decreased after RT for all dose levels. The slope of PSA changes was negative for 176 of 195 patients. By increasing the dosage of radiation, the PSA decreased but these changes were not statistically significant (p = 0.701) and PSA slope as a surrogate end point cannot met the Prentice’s criteria for PC recurrence. Conclusion Significant changes in the dose-response relationship were not observed when the PSA slope was considered as the response criterion. Therefore, although the absolute value of the PSA decreased with increasing doses of RT, the relationship between PSA slope changes and increasing doses was not clear and cannot be used as a reliable response surrogate endpoint.