Administration of several chemotherapeutic drugs, such as bleomycin, busulfan, and gefitinib, often induces lethal lung injury. However, the precise mechanisms responsible for this drug-induced lung injury are still unclear. In the present study, we examined the role of the proinflammatory cytokines IL-18 and IL-1β in the mechanism of bleomycin-induced lung injury. We performed immunohistochemical analysis of IL-18 and IL-18 receptor (R) α chain expression in the lungs of five patients with bleomycin-induced lethal lung injury. Enhanced expression of both IL-18 and IL-18Rα was observed in the lungs of all five patients with bleomycin-induced lung injury. To support the data obtained from patient samples, the levels of IL-1β and IL-18 mRNA and protein, pulmonary inflammation, and lung fibrosis were examined in mouse models of bleomycin-induced lung injury. Intravenous administration of bleomycin induced the expression of IL-1β and IL-18 in the serum and lungs of wild-type C57BL/6 mice. IL-18–producing F4/80⁺ neutrophils, but not CD3⁺ T cells, were greatly increased in the lungs of treated mice. Moreover, bleomycin-induced lung injury was significantly attenuated in caspase-1^−/−, IL-18^−/−, and IL-18Rα^−/− mice in comparison with control mice. Thus, our results provide evidence for an important role of IL-1β and IL-18 in chemotherapy-induced lung injury.