We describe the antibody responses to three strains of canine distemper virus (CDV) isolated from dogs with chronic neurological disease in the Los Angeles area using the naturally occurring sera and cerebrospinal fluids (CSFs) of these animals as probes for comparison. CDV/CDE-2 was derived from a dog with chronic distemper encephalitis, and CDV/ODE-8 and CDV/ODE-10 were derived from dogs with old dog encephalitis. Sera and CSFs were used in autologous (same dog) and allogeneic (different dog) combinations to immune precipitate the [35S]-methionine-labelled H, P, NP, F1, and M polypeptides of the virus-infected cell cultures. The polypeptides were separated by SDS-PAGE and detected by fluorography. There was decreased recognition by the CSF and sera of the polypeptides of the viral isolates in several autologous as well as allogeneic combinations. It is concluded that the immune responses to the CDV strains are not identical, and it is likely that viral mutations occurred after the animals were infected. Some mutations may have contributed to the pathogenesis of distemper encephalitis in these animals and some may have occurred during subsequent passage of the viruses in cell culture. This may explain the decreased recognition of the polypeptides of the viral isolates by the CSF and sera.