The endothelin signaling pathway plays an important role in the migration, proliferation, and differentiation of neural crest cells. Mutations in the gene encoding the endothelin receptor type B (EDNRB) cause three symptoms: aganglionosis, pigmented disorder and hearing loss. In addition, the Ednrb null mice show abnormal splenic microarchitecture with lymphopenia. In this study, we examined whether similar phenotypes are reproduced in three Ednrb-null rat strains that we established previously. AGH-Ednrb(sl)/(sl) strain showed a low white blood cell count, significant size reduction and abnormal microarchitecture of spleen. Thymus displayed a marked reduction in the size, but maintained a normal CD4/CD8 ratio. In contrast, splenic cellularity was reduced to < 15%, and splenic B and T cell numbers were reduced, showing a splenic lymphopenia. Interestingly, Ednrb-null rats in the LE and F344 genetic background did not show these abnormalities. These data show that proper T and B cell development is dependent on the endothelin signaling pathway, however, modifier gene(s) might be differentially expressed in these strain to modulate or compensate for the effect of the Ednrb deficiency.