A clinical neurological syndrome termed peripheral neuropathy (PN) that resembles Marek's disease (MD) occurred at low frequency in a commercial layer strain for several years. Study of chickens from six field cases showed that the PN syndrome could be distinguished pathologically from MD on the basis of several factors, including onset as early as 6 weeks, presence of B-type but not A-type lesions in peripheral nerves, and absence of visceral lymphomas. Serotype 1 MD virus could not be isolated from blood from any chicken or demonstrated in tissues by histochemistry or polymerase chain reaction assays. Moreover, the syndrome was not prevented by MD vaccination, either in the field or in laboratory trials. PN was induced in 3 to 54% of commercial line chickens inoculated at 1 or 6 days of age with whole blood or buffy coat cells from clinically affected donor chickens. Sonicated cells also induced PN, but plasma was ineffective. Chickens did not develop PN if reared in isolators without cellular transfer or when vaccinated solely against MD. However, PN was observed in 9% of 57 B*2/*19 commercial chickens reared in isolators following vaccination against MD, infectious bursal disease, Newcastle disease and infectious bronchitis, suggesting that common vaccines may predispose chickens to PN. The data confirmed a strong influence of the major histocompatibility complex (B-complex) on both naturally occurring and experimentally induced PN with the B*19 haplotype conferring susceptibility compared with other alleles. It is postulated that PN may represent an autoimmune reaction to nerve tissue that may result from response to a combination of common vaccines. These studies confirmed that PN is distinct from MD, provided criteria for its differential diagnosis, identified strategies for its control, and established a model for its experimental induction.