Background: The current study is designed to evaluate the role of PSMA PET/CT for response prediction in prostate cancer (PCa) patients who are candidates for High-Intensity Focused Ultrasound (HIFU) focal therapy (FT). Methods: BetweenOctober 2020 and June 2023, overall 65 patients have been enrolled in our prospective, single-center study. Inclusion criteria were: PSA<20ng/mL, radiological stage ≤T2bN0M0, ISUP grade 1-3, PSMA PET/CT at baseline and at response evaluation 6-12 months post-treatment. Follow up included: PSA at 3, 6 and 12 months. Post-treatment biopsies were scheduled per-protocol at 12 months or earlier if imaging suspicious. Biochemical response and treatment failure were correlated to mpMRI and PSMA PET data, comprising PI-RADS, Primary score, SUVmax, SUVratio, and their variations after HIFU FT. Results: Median age was 67 years (range 53-80), initial PSA (iPSA) was 6.56ng/mL (range 2.25-13.25) and prostate volume was 45mL (range 20-160). The majority of the patients presented with ISUP 1 (66%). mpMRI results were: 14 patients with PI-RADS 1-2 (21.5%) and 51 with PI-RADS 3-4. Baseline Primary scores were: 30 score 1-2 (45%), and 35 score 3-5. Median baseline SUVmax and SUVratio resulted 5.4 (range 1.5-33.2) and 1.43 (range 0.86-9.39), respectively. At 3 months post-HIFU, 23% of the patients obtained a PSA response ≥50%; whereas at 6 months and 12 months, PSA responses were 26% and 45%, respectively. Post-treatment PSMA PET/CT was available in 40 patients. Median SUVmax and SUVratio post-treatment resulted 3.4 (range 1.4-28.4) and 1.1 (range 0.64-10), respectively, with a median ΔSUVmax of 39% and ΔSUVratio of 42%. There was a moderate negative correlation between post-treatment SUVmax and SUVratio with PSA response at 12 months (rho=-0.504, p=0.0280, and rho=-0.521, p=0.0231, respectively), while a positive moderate correlation was confirmed for ΔSUVmax (rho=0.475, p=0.0383). PET parameters were also statistically significantly correlated to treatment failure at 12months (p=0.020, p=0.048 and p=0,04, respectively for SUVmax, SUVratio and Primary), with Primary scores confirmed as predictive on logistic regression (OR=10.5; 95%CI 1.12-98.9). Conclusions: PSMA PET/CT provides useful information for treatment monitoring in PCa patients undergoing HIFU FT. Baseline and post-treatment SUV parameters and Primary score can predict biochemical response and treatment failure at 12 months post-completion.