Cells from 25 mice at different stages of experimental autoimmune encephalomyelitis (EAE) adoptively transferred using lymph node cells sensitized to a synthetic encephalitogenic peptide of myelin basic protein (p87-99) were examined for reactivity to a different encephalitogenic myelin antigen, proteolipid protein (PLP). Cellular reactivity to a synthetic encephalitogenic peptide of PLP (pPLP) was found in 3/5 mice with acute EAE, 4/9 with chronic EAE, 1/6 mice with EAE in remission, and 0/5 during relapse. No proliferation to pPLP was seen in naive mice or in healthy mice immunized with p87-99. Two of 13 mice developed typical EAE after the serial transfer of cells from animals with p87-99-induced EAE had been activated with pPLP in vitro. Controls consisted of recipients of (a) pPLP-activated cells from naive donors or donors immunized with a nonencephalitogenic MBP peptide, (b) cells from mice immunized with MBP activated in vitro with irrelevant antigen, or (c) ovalbumin-activated cells serially transferred from mice with adoptively transferred EAE. No control mice developed signs. These results suggest that during the course of myelin breakdown caused by an immune response to one myelin component (MBP), autoimmune reactivity to at least one additional myelin antigen (PLP) can arise. Furthermore, the acquired cellular reactivity to additional myelin components may be sufficient in some cases to induce disease itself, perhaps lending insight into mechanisms involved in disease progression.