Background: The prostate-specific antigen nadir (nPSA), a strong prognostic factor for prostate cancer, does not occur until several years after definitive radiotherapy. Our aim was to assess an early predictive factor for biochemical failure (BCF) in patients with intermediate- and high-risk prostate cancer treated with definitive radiotherapy. Methods: Between 2007 and 2017, 97 patients with localized prostate cancer underwent radiotherapy at two institutions. We used a pelvic lymph node involvement risk of 15% as the cutoff value, calculated using the Roach formula, to decide whether to deliver prostate and seminal vesicle only radiotherapy (PORT) or whole-pelvis radiotherapy (WPRT). Twenty-seven patients (27.8%) underwent PORT with the prostate receiving 45 Gy (4.5 Gy per fraction) and the other 70 patients (72.2%) underwent WPRT with the prostate receiving 72 Gy (2.4 Gy per fraction). The median equivalent dose in 2 Gy fractions to the prostate was 80.3 Gy based on the assumption that the α/β ratio is 1.5 Gy. Sixty-two patients (63.9%) were treated with androgen deprivation therapy (ADT). Results: The median follow-up time was 40 (range, 10 to 133) months. The 4-year BCF-free survival (BCFS) rate was 87.0%. In the univariate analysis, the nPSA, the nPSA within 12 months (nPSA12), and ADT use were significant predictive factors for BCF. nPSA (p = 0.003) and ADT use (p = 0.041), but not nPSA12 (p = 0.485), were independent predictive factors for BCF in the multivariate analysis. However, there was a strong correlation between nPSA and nPSA12 in this study (r = 0.854, p< 0.001). The receiver operating characteristic curve identified 0.47 ng/ml as the optimal cutoff value of nPSA12 for predicting BCF. The 4-year BCFS rate in patients with nPSA12 < 0.47 ng/ml was 100% in contrast to 71.3% in patients with nPSA12 ≥ 0.47 ng/ml. Conclusions: The nPSA12 has a strong correlation with nPSA and is a considerable predictor of BCF. Therefore, the treatment outcome can be predicted early using nPSA12. Furthermore, ADT can significantly reduce BCF in patients with intermediate- and high-risk prostate cancer.