BACKGROUND AND OBJECTIVE: Patients with Prostate Imaging Reporting and Data System (PI-RADS) 5 lesions are at a high risk of clinically significant prostate cancer (PCa), extracapsular extension, and biochemical recurrence (BCR) after local treatment. Managing these patients with active surveillance (AS) can be particularly challenging when targeted biopsies indicate favorable-risk tumors. This study aims to evaluate the outcomes of patients with PI-RADS 5 lesions managed with AS. METHODS: We analyzed data from 126 patients treated at 16 centers in France, Italy, Switzerland, and Belgium, whose initial magnetic resonance imaging revealed at least one PI-RADS 5 lesion and who subsequently underwent AS. The primary endpoint was BCR-free survival. The secondary endpoints included metastasis-free survival, time to biopsy grade reclassification, and time to AS discontinuation, along with their predictors. KEY FINDINGS AND LIMITATIONS: After a median follow-up of 36 mo after confirmatory biopsies (95% confidence interval [CI] 23-55), BCR was observed in five patients, with the median time not reached. The 5-yr BCR-free survival rate was 88% (95% CI 79-99%). No metastatic progression was reported. Seventeen patients experienced biopsy grade reclassification (median time not reached), and 55 patients discontinued AS. The median time to AS discontinuation was 55 mo (95% CI 46 mo-not applicable). The 5-yr AS discontinuation-free survival rate was 41% (95% CI 30.8-54.6%). On a multivariate Cox regression analysis, baseline prostate-specific antigen density and the percentage of positive biopsy cores were associated with biopsy grade reclassification, AS discontinuation, and BCR. CONCLUSIONS AND CLINICAL IMPLICATIONS: With strict monitoring, AS is a safe management option for patients with PI-RADS 5 lesions and favorable-risk PCa. Limitations are mainly inherent to the retrospective design of this study.