The intrathecal production (ITP) of the immunoglobulins (Ig) G, A, M and D was examined in untreated patients with multiple sclerosis (MS) and controls. Sensitive sandwich enzyme-linked immunosorbent assay systems were applied to the determination of IgA, IgM and IgD levels in the cerebrospinal fluid and plasma from a group of 61 consecutive MS patients (41 relapsing-remitting and 20 secondary chronic progressive MS). Age-related reference limits for all Ig variables were defined in a group of 57 patients with tension headache. ITP of IgG was demonstrated in 85% of the MS patients, ITP of IgA in 41%, of IgM in 44% and of IgD in 18%. Among 9 MS patients with normal IgG index, 3 displayed ITP of IgA, 3 of IgM and 1 of IgD. Plasma IgA was elevated in 20% and plasma IgM in 24% of the MS cases. No significant variation of Ig ITP was demonstrated in a different group of 27 untreated MS patients examined during exacerbation and remission. Among control patients with other inflammatory nervous system diseases, ITP of IgA, IgM and IgD was found more frequently, and of IgG in a smaller percentage compared with MS patients.