This study aimed to analyze technical and clinical factors related to oncological outcomes in patients with localized prostate cancer (PC) who were treated with whole-gland high-intensity focused ultrasound (HIFU). From 2007-2014, patients diagnosed with localized PC who underwent whole-gland HIFU were consecutively included retrospectively. Biochemical failure was defined according to the Phoenix ASTRO guidelines. The relationship between oncological outcomes and technical and clinical factors was evaluated. The study cohort included 428 patients. The median age was 67 years, and the median prostate-specific antigen level was 7.61 ng/mL. Patient risk classifications were low (n = 102), intermediate (n = 240), and high (n = 86). Biochemical disease-free survival rates of patients with HIFU for localized PC in the total, low-, intermediate-, and high-risk groups according to D'Amico risk groups over a median follow-up period of 5 years (range 9-144) were 68.4%, 80.4%, 65.6%, and 61.6%, respectively. In multivariate logistic regression analyses to predict biochemical failure of the treatment, neoadjuvant hormonal therapy (NHT) in the high-risk group (OR 0.225, p = 0.015), and compression method in the low- (OR 0.178, p = 0.030), intermediate- (OR0.291, p < 0.0001), and high-risk (OR 0.316, p = 0.049) groups were significant factors that reduced the risk of biochemical failure after treatment. There were no significant differences in complications between patients treated with compression and those treated conventionally. NHT may potentially improve oncological outcomes for patients in the high-risk group, and compression methods can improve the oncological outcomes of whole-gland therapy with HIFU.