Magnetic resonance imaging (MRI) has resulted in a reduction in the number of patients indicated for prostate biopsy. Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) has recently shown additional value in detecting clinically significant prostate cancer (csPCa). Combining these imaging modalities allows such specific prediction of the presence of csPCa that the need for histological confirmation may be obsolete. We retrospectively analyzed PSMA PET/CT scans performed in the primary staging of PCa in the past 2 yr in our center (n = 451). All 74 patients with a PSMA ligand maximum standardized uptake value (SUVmax) of ≥16 had csPCa (grade group ≥2). Of the 185 patients with a combination of a Prostate Imaging-Reporting and Data System score ≥4 and SUVmax ≥8, 98% had csPCa. A nomogram combining predictive factors should be developed to identify patients in whom biopsy could theoretically be avoided. Nevertheless, biopsy will remain indispensable in patients with indefinite risk of csPCa and can provide important additional information. Using patient data from our center, we found that addition of a special type of scan based on prostate-specific membrane antigen could help in the diagnosis of clinically significant prostate cancer without the need for prostate biopsy. Direct therapy without biopsy confirmation of cancer might be possible for a highly select group of patients.