INTRODUCTION:Oral inoculation with a nontoxic, attenuated strain ofSalmonella typhimuriumreduces tumor burden and improves survival in a mouse model of metastatic colon cancer. These effects are likely mediated byS. typhimurium‐induced increases in hepatic natural killer leukocytes. Cyclooxygenase‐2 inhibitors may mediate antitumor effects through antiangiogenic, immune, or proapoptotic pathways. We hypothesized that cyclooxygenase‐2 inhibitors would act synergistically withS. typhimurium, resulting in additional antitumor effects.METHODS:Four groups of mice were studied: control,S. typhimuriumalone, cyclooxygenase‐2 inhibitor alone, andS. typhimuriumplus cyclooxygenase‐2 inhibitor. Mice were given normal drinking water (control,S. typhimuriumalone) or water with 1,600 parts per million cyclooxygenase‐2 inhibitor (cyclooxygenase‐2 inhibitor alone, andS. typhimuriumplus cyclooxygenase‐2 inhibitor) and orally inoculated with saline (control, cyclooxygenase‐2 inhibitor alone) or 109S. typhimurium(S. typhimuriumalone,S. typhimuriumplus cyclooxygenase‐2 inhibitor). Twenty‐four hours later, all mice underwent laparotomy, and 5 × 104 MCA38 murine adenocarcinoma cells were injected into the spleen. On Day 14, hepatic tumor number and tumor volume was quantitated and hepatic leukocytes were analyzed by flow cytometry.RESULTS:Compared with control mice orally inoculated with saline,S. typhimurium‐treated mice had fewer and smaller tumors; mice treated with cyclooxygenase‐2 inhibitor alone had tumor burden similar to control mice, and mice treated withS. typhimuriumplus cyclooxygenase‐2 inhibitor had fewer and smaller tumors compared with all other groups. Increased liver natural killer cells and decreased CD4+ and CD8+ T cells were observed in bothS. typhimurium‐treated groups. No alterations in hepatic leukocyte phenotype were observed in mice receiving cyclooxygenase‐2 inhibitor alone.CONCLUSION:Oral cyclooxygenase‐2 inhibitor appeared to act synergistically withS. typhimuriumto reduce tumor burden. This combination therapy may have clinical application in the treatment or prevention of hepatic metastases associated with colorectal cancer.