Objective: To assess the performance of systematic TRUS-biopsies in a population-based setting to detect clinically significant PCa (csPCa) in combination with age, clinical tumor category (cT), and prostate-specific antigen (PSA) in men referred for the first biopsy. Methods: We identified all men referred for PCa work-up because of elevated PSA who underwent initial TRUS-biopsies in the nationwide Danish Prostate Cancer Registry (DaPCaR) between January 1st, 1995 and December 31st, 2016, in Denmark. Risk of histologic findings in initial TRUS-biopsies categorized as non–malignant, insignificant PCa, or significant PCa (csPCa). We defined csPCa as any biopsy containing Gleason score 3 + 4 or above as in the PRECISION trial. We assessed risk of csPCa with absolute risk, logistic regression model, and predicted risks. Results and limitations: After exclusions, our cohort included 39,886 men. The diagnostic hit rate for csPCa was 40.8 %. Men with PSA > 20 ng/mL and ≥cT2 harbor a risk >75% for finding csPCa in the first TRUS biopsy-set. Men with cT1 tumors and PSA < 20 ng/mL have a risk of non–malignant histology of at least 58%. Limitations include the high number of exclusions based on missing information. Conclusion: The diagnostic accuracy of systematic TRUS-biopsies is high for men with palpable tumors and high PSA. Our data point to the fact that not all men need pre-biopsy MRI to find csPCa.