Background: Prostate cancer (PCa) screening using prostate-specific antigen (PSA) is controversial. Benign prostate hyperplasia increases PSA in aging men independent of PCa such that PSA’s test performance differs between younger and older men. Age-specific cut-off values might therefore be advisable. The large Norwegian Prostate Cancer Consortium (NPCC) database might be able to contribute with clinically relevant information on age-specific PSA cut-off values. Methods: The Norwegian Prostate Cancer Consortium (NPCC) collected 8 857 761 PSA tests from 1.291.151 men. Results were linked with the date of diagnosis and grade of PCa. Analyses were restricted to men aged 45-75 years. PSA results were grouped into two groups: PCa negative vs PCa positive. The PCa negative group comprised PSA measurements from 2005 to 2015 men being alive and without PCa diagnosis five years after PSA measurement, in total 1 775 986 PSA measurements from 533 216 men. The PCa positive group comprised PSA measurements from 2005 to 2020 of men diagnosed with PCa during this period. PCa diagnoses at autopsy, as incidental finding at cystectomy, with metastases or with PSA > 50 ng/ml were excluded, in total 242 874 PSA measurements from 48 659 men with PCa. Sensitivity, specificity, area under the curve (AUC) as well as top decile and proportion of PCa in the top decile were calculated. Results: For men of 50 years of age, PSA at a threshold of 3 ng/ml yielded a sensitivity and specificity of ~ 95%. In 70–74-year-old men, a 3 ng/ml PSA threshold resulted in a 95% sensitivity but declining specificity of 70%. Maintaining specificity requires increasing PSA cut-off values to 4.5, 6, 7 and 8 ng/ml for men aged 55-59, 60-64, 65-69 and 70-74 years, respectively. The increasing cut-off values for the top PSA decile as well as the decreasing proportion of PCA within the top decile are in line with a declining AUC in older men. Conclusions: PSA test performance declines with increasing age. PCa screening in well-informed men should take into account age adjusted PSA cut-off values.