Multiple sclerosis (MS) is associated with upregulation of both proinflammatory (interferon-gamma, IFN-gamma) and immunosuppressive (transforming growth factor-beta, TGF-beta) cytokines. To examine a possible relation between the MS-related HLA haplotype Dw2 and cytokine profiles, we used in situ hybridization with labeled cDNA oligonucleotide probes to detect transcripts of the T helper type 1 (Th 1) cell related IFN-gamma, the Th2 cell related interleukin-4 (IL-4) and of TGF-beta in blood and cerebrospinal fluid (CSF) mononuclear cells from 62 patients with MS. Compared to patients with other neurological diseases and healthy controls, MS patients had elevated numbers of IFN-gamma, IL-4 and TGF-beta mRNA expressing cells in blood and further augmented in CSF. Although several HLA-Dw2-positive individuals showed very high numbers of cells expressing these cytokines, no significant difference was found in comparison with Dw2-negative patients. However, expression of IL-4 and TGF beta mRNA was significantly increased in patients with shorter duration and minor disability and, for IL-4, in patients still in the relapsing-remitting phase compared to patients with secondary chronic progressive MS. Surprisingly, these changes which favour a beneficial, disease-downregulating effect of IL-4 and TGF-beta in MS, were found to be confined to HLA-Dw2-positive patients. Our findings suggest that the HLA phenotype does not influence the overall level of immune reactivity in MS, but may distinguish subgroups characterized by particular cytokine expression patterns.