Our earlier results demonstrated that clinically relevant concentrations of unconjugated bilirubin (UCB) possessed immunotoxic effects. Whole-body irradiation (WBI) with 1to 6 Gy leads to acute radiation syndrome, immunosuppression, and makes the host susceptible to infection. Since hyperbilirubinemia has been shown to be associated with several types of cancer, the present studies were undertaken to evaluate the radiomodifying effects of UCB in radiation-exposed mice having elevated levels of UCB. Pretreatment of spleenic lymphocytes with UCB (1–50 μM at UCB/BSA  ratio <1) augmented radiation- induced DNA strand breaks, MMP loss, calcium release, and apoptosis. Combination treatment of mice with UCB (50mg/kgbw) followed by WBI(2Gy)0.5hlater, resulted insignificantly increased splenic atrophy, bonemarrowaplasia, decreased counts of peritonealexudate cells, and different splenocyte subsets suchasCD3þ T, CD4þ T, CD8þ T, CD19þ B, andCD14þ macrophages as compared to either UCB or WBI treatment. Hematological studies showed that WBI-induced lymphopenia, thrombocyto- penia, and neutropenia were further aggravated in the combination treatment group.UCB pretreatment of mice potentiated WBI-induced apoptosis and decreased WBI-induced loss of functional response of various immune cells leading to augmentation of immunosuppression and infection susceptibility caused by WBI. In an acute bacterial peritonitis model, UCB pretreatment of mice significantly increased WBI-induced proinflammatory cytokines, nitricoxide, and peritoneal bacterial load resulting in increased infection and death. Studies using the pharmacological inhibitor of p38MAPKdemon- strated the involvement of p38 MAPK activation in the inflammatory cascade of peritonitis.These findings should prove useful in understanding the potential risk to hyperbilirubinemic patients during radiotherapy and victims of acute radiation exposure in the course of radiation accidents.