Infection of mice with Salmonella enteritidis 11RX has been shown previously to cause nonspecific immune stimulation and, consequently, resistance to subsequent challenge with a variety of transplantable tumors. The present study has examined the effect of infection with this organism in a chemical carcinogenesis system. Colonic tumors were induced in LACA and BALB/c x C57BL/6JF1 mice by weekly s.c. injection of 1,2-dimethylhydrazine (15 mg/kg) for 28 weeks. Infection of mice p.o. with live S. enteritidis 11RX at 8-week intervals during 1,2-dimethylhydrazine administration protected both strains against colon tumorigenesis. Significantly fewer infected than control BALB/c x C57BL/6JF1 mice had colonic tumors at or before termination of the experiment (34 or 40 weeks) (p less than 0.001 in all cases). Comparable results were obtained with both male and female mice. The difference in tumor incidence between control and infected LACA mice was not statistically significant, however; the number and size of the lesions was greater in control mice (p less than 0.02). Although it has not been proven that the protective effect is mediated by the immune system, the results are consistent with the operation of a macrophage-mediated surveillance system. It is suggested that enteric infections should be considered as a possible contributing factor in the epidemiology of human colonic cancer.