An antibody was detected in the sera from patients with systemic lupus erythematosus (SLE) and central nervous system (CNS) involvement that reacted with a 50-kD antigen in the plasma membrane of brain synaptic terminals. The 50-kD antigen was solubilized with Triton X-100 from preparations enriched with synaptic plasma membranes, and was partially purified by molecular sieve filtration column chromatography. The sera of 19 of 20 CNS-SLE patients showed strong to moderate immunoreactivity with the 50-kD protein in Western blots. Immunoreactivity with the 50-kD protein was also detected in the cerebrospinal fluid of CNS-SLE patients. Control sera from healthy individuals did not react with the 50-kD protein. Low to background reactivity was detected in 35% of a group of SLE patients without CNS manifestations, and in 3% of patients displaying other connective tissue diseases. A total of 100 individuals were tested in this study. Purified autoantibodies to the 50-kD protein from CNS-SLE patients were used for immunofluorescent labeling of neuroblastoma cells. The immunofluorescent staining revealed a distinct macular distribution pattern on the surface of the cell membrane. Taken together, the data suggest that the 50-kD protein may be an important target for autoantibodies, preponderantly found in CNS-SLE patients, and that the antigen may play a role in the pathogenesis of some neurological manifestations in SLE.