In order to investigate possible immunopathogenic mechanisms in the recurrence of uveitis, cross-reactive proteins were tested for their capacity to induce experimental uveitis. Guinea pigs were immunized with porcine serum albumin (PSA) in complete Freund's adjuvant (CFA) by subcutaneous injection. Fourteen or 28 days after the immunization, PSA, bovine (BSA), sheep (SSA), equine (ESA), rabbit (RSA) serum albumin, bovine gamma globulin (BCG) or ovalbumin (OA) was injected into the vitreous. Uveitis occurred in the eyes injected with PSA, BSA, SSA, ESA or RSA, but not BGG or OA. Serum antibodies and erythematous delayed-type skin reactions against PSA, BSA, SSA, ESA and RSA were positive in animals immunized with PSA in CFA. In an adoptive transfer study, humoral and cellular immunity recognized cross-reactive antigens and uveitis developed. Once a guinea pig is sensitized, uveitis may occur or recur from subsequent intravitreal challenge by antigens that are not completely the same but have a cross-reactivity with the immunizing antigen.