Increased diagnoses of silent prostate cancer (PCa) have led to overtreatment and consequent functional side effects. Focal therapy (FT) applies energy to a prostatic index lesion treating only the clinically significant PCa focus. We analysed the potential predictive factors of FT failure. We collected data from patients who underwent robot-assisted radical prostatectomy (RARP) in two high-volume hospitals from January 2017 to January 2020. The inclusion criteria were: one MRI-detected lesion with a Gleason Score (GS) of ≤7, ≤cT2a, PSA of ≤10 ng/mL, and GS 6 on a random biopsy with ≤2 positive foci out of 12. Potential oncological safety of FT was defined as the respect of clinicopathological inclusion criteria on histology specimens, no extracapsular extension, and no biochemical, local, or metastatic recurrence within 12 months. To predict FT failure, we performed uni- and multivariate logistic regression. Sixty-seven patients were enrolled. The MRI index lesion median size was 11 mm; target lesions were ISUP grade 1 in 27 patients and ISUP grade 2 in 40. Potential FT failure occurred in 32 patients, and only the PSA value resulted as a predictive parameter (p < 0.05). The main issue for FT is patient selection, mainly because of multifocal csPCa foci. Nevertheless, FT could represent a therapeutic alternative for highly selected low-risk PCa patients.