We read with interest the Research Letter by Howard1 about declines in prostate cancer incidence among men 75 years and older after changes in screening recommendations. Along with the valuable comments of Katz,2 who clearly emphasized that the harms of screening may largely outweigh the benefits in younger men as well, it is now undeniable that a rather different screening strategy should be planned, based on the use of more specific and clinically useful biomarkers. The leading drawbacks of total prostate-specific antigen (PSA) testing are indeed represented by overdiagnosis and inability to reliably differentiate indolent from aggressive cancers. However, there is now solid evidence that the Prostate Health Index (PHI) has a diagnostic specificity that is 2- to 4-fold higher than total PSA at identical sensitivity thresholds.3 A significant relationship between Gleason score and PHI was also found in men with total PSA between 2 and 10 ng/mL (to convert to micrograms per liter, multiply by 1), which is thereby crucial for identifying those men harboring more clinically relevant prostate cancers and increased likelihood of death.4 Even more interestingly, a strategy entailing the combination of total PSA and PHI was also proven to be less expensive than a PSA-only strategy, with gains of up to 0.08 in quality-adjusted life years.5