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Purpose To compare the clinical outcome of males with low-risk and favorable intermediate-risk prostate cancer managed within a standardized modern protocol of active surveillance. Materials and Methods This was a prospective cohort study with strict and expanded active surveillance criteria in males with prostate cancer. Baseline assessment included multiparametric magnetic resonance imaging (mpMRI), extended systematic biopsy, and software-based MR-targeted biopsy. Follow-up included biannual prostate-specific antigen (PSA) check, mpMRI, and control biopsy once a year for the first 2 years, and afterward mpMRI every 2 years with additional tests as clinically indicated. The primary outcome was the transition rate to active treatment. Results A total of 51 patients were included: 17 (33%) and 34 (67%) followed protocols of strict (study arm 1) and expanded (study arm 2) active surveillance criteria, respectively. Median age and PSA were 65 years (IQR, 60–69 years) and 5.3 ng/mL (IQR, 4.5–7.7 ng/mL), respectively. At baseline, a median of 2 (IQR, 1–3) cores were positive out of 13 (IQR, 12–14) cores; 22 males (43%) had visible mpMRI lesions. Eight males (24%) in study arm 2 had Gleason score 3+4. After a median follow-up of 36 months (IQR, 24–48 mo), no patient in study arm 1 compared with 17 patients (33%) in arm 2 underwent active treatment (p<0.0005). Conclusions Although expanding eligibility criteria leads to a greater transition rate to active treatment, active surveillance should be contemplated in well-selected males with favorable intermediate-risk prostate cancer as the curability window seems to be maintained.