To explore the responses of host cell after infection with live Salmonella compared with phagocytosis to dead bacteria, the responses of mouse macrophage after infection with Salmonella enteritidis C50041 and the fixed C50041 (C50041-d) were analyzed. Results indicated that the cytotoxicity induced by C50041 was stronger than C50041-d. Similar changing trends of mitochondrial membrane potential, intracellular concentration of calcium ions, reactive oxygen species and nitric oxide were found between C50041 and C50041-d infection. But the cell responses against C50041 were earlier and stronger than C50041-d. LC3 expression of macrophage induced by C50041 was lower than C50041-d. C50041 significantly inhibited the production of tumor necrosis factor and interleukin (IL)-6. Whereas intracellular caspase-1 activation and IL-1β release induced by C50041 were stronger than C50041-d, caspase-1 activation and IL-1β release are the innate defense responses of macrophage. Therefore, it will be beneficial to explore the use of this pathway in the control of Salmonella infection.