Objective To investigate the role of RIP3 (receptor-interacting protein 3), which is a key molecule in regulating programmed cell necrosis, in H1N1 influenza virus infection. Methods RIP3 knockout (RIP3 ^{- / -} ) and wild-type (WT) mice were infected by influenza virus H1N1 PR8 at a dose of 5. 25 × 10³ TCID₅₀ (50% tissue culture infective dose). Changes of clinical signs, survival, and body weight of those mice were monitored daily for 14 consecutive days. Six mice from each group were sacrificed at 3 and 7 days post-infection (d. p. i. ), from which whole lungs were harvested. Some of the lobes were fixed in 4% paraformaldehyde for histopathological assessment and the rest were split and stored at -80℃ for further analysis. Real-time quantitative PCR and cytometric bead array (CBA) were performed to detect viral loads in lungs and inflammatory cytokines in supernatants of lung homogenates. Results Both groups showed severe symptoms after the infection of PR8. The RIP3 ^{- / -}mice with PR8 infection showed a high survival rate (50%)compared with the control group (12. 5%) ( P < 0. 05). The body weight loss of WT was greater than that of RIP3 ^{- / -}mice from 3 d. p. i. , but there was no significant difference between these two groups. No significant differences in viral loads and lung weight to body weight ratio were also observed between the two groups at 3 and 7 d. p. i. Pathological changes in RIP3 ^{- / -} mice were less severe than those in WT mice. CBA detection assay revealed that the levels of proinflammatory cytokines in the lungs of RIP3 ^{- / -} mice were lower than those in WT mice. Conclusion RIP3 plays a pathogenic role in mice infected with 5. 25 ×10³ TCID₅₀of influenza virus H1N1 PR8 by promoting inflammatory responses.