Salmonella enterica serovar Typhimurium (S. Typhimurium) inhabits a wide range of hosts, including poultry, and causes acute gastroenteritis in humans that may result in death. Superoxide dismutase (SOD) is an important antioxidant enzyme present in nearly all living cells exposed to oxygen. Recently, we reported the novel roles of SOD in serum resistance and biofilm formation in S. Typhimurium. This study was designed to explore the effect of infection with sodA mutant of S. Typhimurium on the autophagic response of macrophages. Murine macrophage cell line RAW264·7 was infected with wild-type (LSM52), a sodA deletion mutant (LSM52ΔsodA) and complemented strain (LSM52CΔsodA). We found that sodA deletion triggered remarkable autophagic responses in infected cells, shown as higher concentrations of LC3-II or Beclin-1 than those infected with the wild-type or complemented strain during the first hour post-infection in S. Typhimurium. Consistent with these results, the number of viable bacteria in cells infected with the sodA mutant was significantly lower than those infected with wild-type or complemented strains at 1 h, 2 h and 3 h post-infection in S. Typhimurium. All results indicated that infection with sodA mutant of S. Typhimurium leads to up-regulation of autophagy in Raw264·7 macrophages. SIGNIFICANCE AND IMPACT OF THE STUDY: Autophagy plays an important role in Salmonella infection although the role of autophagy in Salmonella infection remains unclear. This study was designed to explore the effect of sodA on the autophagic response of macrophage. We found that infection with sodA mutant of Salmonella Typhimurium could lead to up-regulation of autophagy in Raw264·7 macrophages.