To quantify the extent to which a clinically significant prostate cancer mortality reduction due to screening could have been masked by control arm screening (contamination) in the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial. We used three independently developed models of prostate cancer natural history to conduct a virtual PLCO trial. Simulated participants underwent pre-trial screening based on population patterns. The intervention arm followed observed compliance during the trial then resumed population screening. A contaminated control arm followed observed contamination during the trial then resumed population screening, while an uncontaminated control arm discontinued screening upon entry. We assumed a clinica The virtual trial reproduced observed incidence, including stage and grade distributions, and control arm mortality after 10 years of complete follow-up. Under the assumed screening benefit, the three models found that contamination increased the mortality rate ratio from 0.68-0.77 to 0.86-0.91, increased the chance of excess mortality in the intervention arm from 0-4 % to 15-28 %, and decreased the power of the trial to detect a mortality difference from 40-70 % to 9-25 %. Our computer simulation models indicate that contamination substantially limited the ability of the PLCO to identify a clinically significant screening benefit. While the trial shows annual screening does not reduce mortality relative to population screening, contamination prevents concluding whether screening reduces mortality relative to no screening.