Two large, randomized studies have demonstrated a prostate cancer-specific survival benefit to prostate cancer screening using the prostate-specific antigen (PSA) assay. Yet, the US Preventive Services Task Force recently recommended against PSA-based screening for prostate cancer, claiming it results in more harm than good, given concerns regarding overtreatment. The purpose of this article is to characterize the patients with colorectal cancer who are most likely to benefit from PSA-based screening for prostate cancer. Because the survival benefit due to PSA-based screening does not manifest until 7 years after screening is initiated, we conclude that PSA screening is most appropriate for men with a remaining life expectancy of at least 10 years. Accordingly, younger men with stage I-II colorectal cancers at diagnosis (or stage III colorectal cancer that has not recurred 5 years after treatment) who have no or minimal comorbidities and who are at increased risk for either a diagnosis of prostate cancer or mortality secondary to prostate cancer (patients who have a positive family history or are African-American, respectively) are most likely to experience more good outcomes than harmful ones as a result of undergoing PSA-based screening.