There are no standard methods to predict response to treatment or outcome of stage IV melanoma. Our previous assessment of peripheral blood mononuclear cells (PBMC) from immunized patients demonstrated that interleukin (IL)-10 expression might be associated with prognosis. However, PBMC are a mixture of CD4+ cells, CD8+ cells, and monocytes. This study identified the subset of PBMC responsible for IL-10 expression and evaluated the prognostic value of IL-10 expression in immunized stage IV patients. Eighty-seven patients with stage IV melanoma were randomly selected from our database. All patients had received an allogeneic melanoma whole-cell vaccine (Canvaxin) after complete resection of clinical disease. Blood samples had been collected serially during Canvaxin administration and cryopreserved. Intracellular IL-10 expression was assessed by double staining fluorescence-activated cell sorter. CD14+ monocytes are the predominant PBMC producing IL-10. Sixteen weeks after treatment (week 16), IL-10 levels were significantly (P=0.02) higher in poor-survival patients than those with favorable outcomes. Patients were separated into 2 groups on the basis of the CD14+ monocyte IL-10 response: either increasing or decreasing IL-10 expression from preimmunization (week 0) to week 16 blood draws. Patients with increasing IL-10 levels had significantly shorter survival than those whose IL-10 levels decreased at week 16 (P<0.0001). Multivariate analysis demonstrated that trends in IL-10 levels inversely correlated with survival (P<0.0001). We conclude that CD14+ monocytes are the dominant cellular source of IL-10 among PBMC and that changes in IL-10 expression may serve as an immunologic-based surrogate for predicting outcome for stage IV patients after surgical resection.