The use of Salmonella as a potential antitumor agent has been investigated, but innate immunity against this bacterium reduces the efficacy of its tumor-targeting and antitumor activities. The purpose of this study was to investigate the modulation of the tumor-targeting efficiency of Salmonella enterica serovar choleraesuis by modifying the immune response to these bacteria by coating them with poly(allylamine hydrochloride) (PAH), designated PAH-S.C. To evaluate this modulation, we used naïve mice and mice immunized with Salmonella to study the role of the preexisting immune response to the antitumor activity of PAH-S.C. When anti-Salmonella antibodies were present, the invasion activity, cytotoxicity, and gene transfer of Salmonella was significantly decreased, both in vitro and in vivo. Treatment with PAH-S.C. resulted in delayed tumor growth and enhanced survival in immunized mice. Furthermore, immunohistochemical studies of the tumors revealed the infiltration of neutrophils and macrophages in immunized mice treated with PAH-S.C. These results indicate that Salmonella encapsulation effectively circumvented the Salmonella-specific immune response.