OBJECTIVE: We used a whole blood assay to characterize the immune system's response after cardiopulmonary bypass (CPB) in children to identify the risk for postoperative infections. We assessed the impact of CPB on histone methylation as a potential mechanism for altering gene expression necessary for the immune system's capacity to defend against infections. METHODS: We prospectively enrolled patients less than 18 years old undergoing heart surgery requiring CPB at C.S. Mott Children's Hospital. Blood was obtained from patients before CPB, on CPB, and on postoperative days 1, 3, and 5. Ex vivo lipopolysaccharide-induced tumor necrosis factor-alpha production measured the capacity of the immune system. Serum cytokines were measured using a multiplex assay. Chromatin immunoprecipitation to detect histone modifications at the interleukin (IL) 10 promoter was performed on circulating mononuclear cells from a subgroup of patients. RESULTS: We enrolled 92 patients, and postoperative day 1 samples identified a subpopulation of immunocompetent patients at low risk for infections with a specificity of 93% (confidence interval [CI], 83%-98%) and a negative predictive value of 88% (CI, 77%-95%; P = .006). Patients classified as immunoparalyzed had serum IL-10 levels 2.4-fold higher than the immunocompetent group (mean, 14.3 ± 18.3 pg/mL vs 6.0 ± 5.0 pg/mL; P = .01). In a subgroup of patients, we identified a greater percent of the "gene on" epigenetic signature, H3K4me3, associated with the IL-10 promoter after CPB. CONCLUSIONS: Our data demonstrate that immunophenotyping patients after CPB can predict their risk for the development of postoperative infections. Novel mechanistic data suggest that CPB affects epigenetic alterations in IL-10 gene regulation.