AbstractA substrain of the Lewis rat, Lew/Mol, differing from ordinary Lewis rats in that it is hardly susceptible to the induction of experimental autoimmune encephalomyelitis (EAE) is described. The Lew/Mol rats did not mount a host‐vs. ‐graft response towards cells from an EAE‐susceptible substrain of Lewis rats (Lew/Mai) and vice versa. This argues against the possibility that the origin of Lew/Mol rats involves accidental cross‐breeding with other rat strains. Thus the EAE‐resistance in Lew/Mol rats is interpreted as being due to a mutation(s) in a gene(s) regulating the susceptibility to EAE. Specific pathogen‐free Lew/Mol rats were more resistant to EAE induction than Lew/Mol rats bred under conventional conditions, emphasizing the importance of environmental factors. Neither cyclophosphamide treatment nor increased age resulted in marked susceptibility in the Lew/Mol rats, although aging apparently had some effect, as a few animals did show neurological signs. Approximately half of (Lew/Mol × Lew/Mai) F1 hybrids developed EAE with neurological signs. In this respect, Lew/Mol rats differ from another recently described EAE‐resistant substrain of the Lewis rat (LeR).