Experimental autoimmune uveitis (EAU) in the Lewis rat has been regarded as an acute and monophasic disease. Uveitis can be induced by immunization with retinal soluble antigen (S-Ag), interphotoreceptor retinoid-binding protein (IRBP) or their peptide derivatives (PDSAg from S-Ag and R14 from IRBP) in CFA as well as by the transfer of activated, antigen-specific T cells. Previously, it has been shown that adoptively transferred, IRBP peptide-specific, but not S-Ag peptide-specific T cells can induce relapsing uveitis in rats. We observed spontaneous recurrences of intra-ocular inflammation even after immunization with R14 in CFA and were able to experimentally re-induce uveitis in rats previously immunized with autoantigen peptide in CFA. The efficiency of re-induction was dependent on the mode of pre-treatment [immunization or adoptive transfer (AT)] as well as on the antigen itself. Primary PDSAg-responses prevented subsequent re-induction of disease much more efficiently than primary R14-mediated EAU. In our model, the suppressive effect of CFA did not play a key role in preventing re-induction or spontaneous relapses. Furthermore, epitope spreading could not be demonstrated as a cause for recurrent inflammation. These data suggest that autoimmune responses with different antigen specificities could underlie similar clinical pictures while being differently regulated, which may help explain the variations in the disease courses in patients and the differential responses to therapeutic modalities.