Ocular onchocerciasis results from immune recognition of parasite proteins released into the eye by degenerating microfilariae. Previous studies have shown that pathology similar to human ocular onchocerciasis can be induced in sensitized mice by intracorneal injection with Onchocerca volvulus antigens. In the current study, we used this murine model to map the segments of O. volvulus protein disulfide isomerase (OvPDI) associated with the development of corneal pathology. Subclones of OvPDI were constructed encompassing one or more predicted T cell epitopes. Keratitis was induced in BALB/c mice after subcutaneous immunizations with OvPDI, followed by intracorneal challenge of OvPDI constructs. Truncated OvPDI proteins containing amino acids 450-481 of OvPDI were found to induce keratitis, whereas constructs that did not include this region did not induce corneal pathology. Consistent with this observation, two peptides derived from the 450-481 region stimulated T cell proliferation to a greater degree than control carrier protein. DNA sequence analysis of cDNAs encoding OvPDI from blinding and non-blinding strains of O. volvulus indicated no differences in the primary amino acid sequence of the 450-481 domain. Immunization of animals with OvPDI induced antibodies recognizing a 55 kDa host protein, identical to the predicted molecular weight of the mouse PDI homologue. Together, these data implicate specific antigenic epitopes of OvPDI in the development of O. volvulus mediated corneal pathology.