The humoral immune response to canine distemper viral antigens in gnotobiotic dogs experimentally infected with canine distemper virus was studied by the complement fixation and serum neutralization tests. Antibody titers measured by both serologic methods varied inversely with the severity of disease produced. Recovered dogs demonstrated the highest titers of antibody, whereas fatally infected dogs had little or no antibody activity in their sera. A third group of dogs, characterized by chronic persistent infection, had intermediate levels of anitbody to canine distemper virus. Preliminary characterization of the viral antigens involved in the complement fixation test indicated that at least two antigenic components were involved. One antigen was soluble in ether and was heat-labile, whereas the other was relatively heat-stable and was unaffected by treatment with ether. No evidence for serologic cross-reaction between viral and central nervous system components was found. A vigorous antibody response to envelope antigen determinants in addition to core determinants distinguished immune dogs from persistently infected dogs. The results of this study suggest that the inability to produce antibodies to envelope antigens may be a crucial factor in the establishment of a persistent infection with canine distemper virus in these dogs.