Background/Purpose: Spotting lethal (sl) rats, a model for Hirschsprung's disease, recently have been found to carry a deletion in the endothelin B (ETB) gene, causing functional lack of ETB receptors. The ETB receptor mediates, together with and in counterbalance to the ETA receptor, endothelin actions on vessels, cell proliferation, and migration. The authors investigated the effect of homozygosity (sl/sl) or heterozygosity (+/sl) on phenotype, intestinal morphology, and survival. Methods: Weight, circumference, and serum albumin were measured. Histological tests of major organs and immunoperoxidase reaction for Peripherin, glial fibrillary acid protein (GFAP), and S-100 in small and large intestine were performed. Peripherin-immunostained sections of colon and jejunum were analyzed morphometrically. Screening for sepsis included search for enterocolitis, bacterial infection, endotoxin, and iNOS mRNA. Results: SI/sl rats died within 4 weeks of life, showing an early and a later death group. Serum albumin levels were decreased in sl/sl rats, whereas signs of sepsis were rare. Immunostaining uncovered alterations in nerve and glial cells in the whole gut of sl/sl rats, and to a subtle degree also in +/sl rats, which appear clinically normal. Morphometric quantification yielded statistically significant alterations in sl/sl rats only. No obvious abnormalities were found in other organs. Conclusions: SI/sl rats die from malnutrition rather than sepsis, too early for ischemic complications to occur. Rats of the later death group are a suitable model for studying the ETB receptor in vivo. Subtle abnormalities in the enteric nervous system of heterozygous rats underline the critical role of the “gene dose” for functional compensation.