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Purpose: While prostate-specific antigen (PSA) screening protocols vary, many clinicians have anecdotes of screened men with low PSA levels that rise significantly and are associated with high-risk prostate cancer (PC). We sought to better understand the frequency of high-risk cases that appear suddenly in a screened population., Methods: We utilized data from a Commercial and Medicare advantage claims database to identify all US men ages 50 and above undergoing PSA screening who then had a sudden interval rise in PSA (e.g., PSA ≥ 20) and diagnosis of PC. We determined associations with age, race, screening intensity, and baseline PSA levels., Results: In all, 526,120 men met entry criteria with an average age of 60.7 and follow-up of 5.6 years. As the baseline PSA increased, the rate of high-risk PC increased from 2/10,000 persons among men with the lowest baseline PSA (<1 ng/ml) to 14/10,000 person-years among men with a baseline PSA < 5 ng/ml. Moreover, as a man's age at baseline PSA increased, the rate of high-risk PC also increased. In contrast, the incidence of high-risk PC did not vary significantly by race/ethnicity. More screening PSAs and shorter intervals between PSA screenings were associated with a lower incidence of high-risk PC., Conclusions: The incidence of high-risk PC in a screened population is low (<0.1%). Our findings suggest that systematic screening cannot eliminate all PC deaths and provide an estimate for the risk of the rapid development of high-risk cancers that is comparable to that observed in active surveillance populations., (© 2020 Wiley Periodicals LLC.)