SJL/J mice were immunized with human PLP as well as encephalitogenic PLP peptides 139-151 and 178-191 and the resulting antibody responses examined for immunochemical specificity employing a panel of 17 synthetic PLP peptide ligands. All animals had demonstrable circulating titers of antibodies early in the humoral immune response to their respective encephalitogens, however, there was no clear qualitative correlation between antibody responses and the induction of EAE. In the majority of PLP immunized animals, determinant-specific antibody populations, including those against encephalitogenic centers, were not detectable in the presence of an anti-PLP antibody response. Antiencephalitogenic peptide antibodies were present in both 139-151 and 178-191 immunized animals regardless of clinical/histologic status. Neither group produced cross-reactive anti-PLP antibodies as detected by ELISA. In animals immunized with peptide 139-151, only anti-139-151 antibody specificities were noted. In contrast, all animals immunized with peptide 178-191 had an antibody population cross-reactive with three other PLP peptides: 97-110, 209-217, and 215-228. As humoral immune responses can be demonstrated against PLP-specific encephalitogenic epitopes, the significance of these B cell responses should be considered in the context of their potential role in the development, modulation, and/or potentiation of EAE.