Dextran sulfate sodium (DSS)-induced murine colitis represents an experimental model for human inflammatory bowel disease. The aim of this study was to screen various inbred strains of mice for genetically determined differences in susceptibility to DSS-induced colitis. Mice of strains C3H/HeJ, C3H/HeJBir, C57BL/6J, DBA/2J, NOD/LtJ, NOD/LtSz-Prkdc(scid)/Prkdc(scid), 129/SvPas, NON/LtJ, and NON.NOD-H2g7 were fed 3.5% DSS in drinking water for 5 days and necropsied 16 days later. Ceca and colons were scored for histological lesions based on severity, ulceration, hyperplasia, and area involved. Image analysis was used to quantitate the proportion of cecum ulcerated. Histological examination revealed significant differences among inbred strains for all parameters scored. In both cecum and colon, C3H/HeJ and a recently selected substrain, C3H/HeJBir, were highly DSS susceptible. NOD/LtJ, an autoimmune-prone strain, and NOD/LtSz-Prkdc(scid)/Prkdc(scid), a stock with multiple defects in innate and adoptive immunity, were also highly DSS susceptible. NON/LtJ, a strain closely related to NOD, was quite DSS resistant. The major histocompatibility (MHC) haplotype of NOD mice (H2g7), a major component of the NOD autoimmune susceptibility, was not crucial in determining DSS susceptibility, since NON mice congenic for this MHC haplotype retained resistance. C57BL/6J, 129/SvPas, and DBA/2J mice showed various degrees of susceptibility, depending upon the anatomical site. A greater male susceptibility to DSS-induced colonic but not cecal lesions was observed. In summary, this study demonstrates major differences in genetic susceptibility to DSS-induced colitis among inbred strains of mice. Knowledge of these strain differences in genetic responsiveness to acute inflammatory stress in the large intestine will permit design of genetic crosses to elucidate the genes involved.