The presence of complement-fixing antibodies against brain antigens was tested in paired serum and cerebrospinal fluid (CSF) samples from 60 multiple sclerosis (MS) patients, 15 patients with chronic myelopathy of undetermined cause (CM) and 60 control patients. Six MS sera, 34 MS CSF, 4 CM sera, 3 CM CSF, 4 control sera and 1 control CSF gave positive reactions either with a lipid extract or a saline extract of normal human brain. The proportion of anticomplementary CSF was significantly higher in the MS group than in the control group (15% vs 0%, P less than 0.01). The reactivity of a large number of individual positive samples was further investigated. Seven antibody specificities were discerned in the MS samples. Most samples reacted with non-lipid antigens, the dominating being a heat-labile, nonlipid component associated with CNS myelin. Antibodies to cerebroside and sulfatide were detected in a few patients. A number of samples reacted with cholesterol in combination with a variety of lipids. Positive samples from the CM patients exhibited a similar heterogeneity. In the control group positive reactions were seen in one patient with systemic lupus erythematosus (SLE), two patients with rheumatoid arthritis (RA), and one with a spinal meningioma. The reaction patterns of these patients were different from those commonly seen in MS patients. The complement-fixing antibrain antibodies in MS CSF are usually of IgG class (Ryberg 1976). This applies also to the positive MS sera in this study. The distribution of the antibodies between serum and CSF indicated, in several cases, an intrathecal synthesis. All of a number of human brains, including one MS brain, contained all 6 antigens (haptens) reactive in saline extracts. Antibodies to tissues outside the CNS were rarely detected in MS patients. The varied humoral autoimmune response in MS might reflect a heterogeneity in the MS patients, the disease itself or its causative agent.