A major problem of serum prostate-specific antigen (PSA) for predicting prostate cancer risk is diagnostic uncertainty. To detect circulating macrophages with phagocytized fragments (eg, PSA) of prostate tumor cells and determine if the number of circulating PSA-containing macrophages can help differentiate between benign and malignant prostate disease, we collected mononuclear cells from peripheral blood. After labeling the macrophages, phagocytized PSA was detected by incubating the cells with a phycoerythrin-conjugated PSA monoclonal antibody. Flow cytometric analysis was performed. A significant difference was observed in the mean+/-SD percentage of activated macrophages (CD14+/CD16+) between malignant (28.8%+/-13.0%) and benign conditions (17.3%+/-6.8%; P< .0001). A significant increase was detected in the percentage of PSA-containing macrophages in prostate cancer (17.7%+/-12.3%) vs benign disorders (3.6%+/-1.9%; P< .0001) and between localized (10.5%+/-3.4%) and metastasized prostate carcinoma (26.3%+/-14.3%; P= .0002). The new method for detecting circulating PSA-containing macrophages can be suitable for differentiating prostate cancer from benign conditions and, possibly, low-risk from more aggressive prostate cancer.