Interleukin (IL)-10 and IL-12 production is decreased in peripheral blood mononuclear cells of patients with mild asthma. Using whole blood culture and flow cytometry we examined whether monocyte heterogeneity influenced IL-10 and IL-12 production in subjects with severe asthma. We demonstrated that IL-10 release in LPS-stimulated whole blood culture was decreased in patients with severe persistent asthma compared to those with mild asthma and controls (P = 0.04 and P < 0.001, respectively). In asthmatic patients, the percentage of CD14(+)CD16(+) cells was higher than that from normal subjects (P = 0.04). Severe asthmatics showed significantly less positive staining for IL-10 and IL-12 (P < 0.001 and P = 0.02, respectively) after stimulation in monocytes, compared to mild asthmatics and controls in both CD14(+)CD16(+) and CD14(+)CD16(minus sign) cells. These results suggest that IL-10 synthesis is attenuated in severe persistent asthma compared to mild asthma and that this cannot be explained by the increase in the CD14(+)CD16(+) monocytes in asthma.