Data indicate that 58% of the variability in prostate cancer incidence is explained by the significant contributions of inherited genetic factors to prostate cancer risk. To determine if adherence to a healthy lifestyle can offset the increased genetic risk of prostate cancer, including progression to lethal disease, researchers quantified the genetic risk of prostate cancer in more than 10,000 men with a validated polygenic risk score (PDS). They also applied a validated lifestyle score for lethal prostate cancer (including healthy weight, vigorous physical activity, not smoking, and high consumption of tomatoes, fatty fish, and reduced intake of processed meat) and examined overall and lethal prostate cancer incidence. Men in the highest genetic risk quartiles had a 5.4-fold increased risk of overall prostate cancer and a 3.5-fold greater risk of lethal prostate cancer when compared with those in the lowest quartile. Among men in the highest quartile, healthy lifestyle adherence was significantly associated with decreased lethal prostate cancer risk when compared with the least healthy lifestyle, but it was not associated with decrease risk of overall prostate cancer. Among men with highest genetic risk, a healthy lifestyle at study entry was associated with a lifetime cumulative incidence of lethal prostate cancer of 3%, compared with 6% for those with the least healthy lifestyle and 3% for the population average.