Tumor necrosis factor-alpha (TNF-alpha) is a potent mediator produced by activated T lymphocytes and macrophages, which may play a role in the pathogenesis and development of multiple sclerosis (MS) and HTLV-1-associated myelopathy (HAM). The first step in the induction of many biological effects elicited by TNF-alpha is its binding to specific cell surface receptors. A soluble form of TNF receptor (sTNF-R) can be detected in the body fluid. We measured sTNF-R levels in the sera and cerebrospinal fluid (CSF) of patients with either MS or HAM, and evaluated the correlation between this mediator and disease activity. The levels of sTNF-R in the sera and CSF of patients with MS were significantly increased compared with controls, particularly patients with acute relapsing MS during an exacerbation (P < 0.001). CSF levels of sTNF-R showed a strong correlation with those of TNF (r = 0.716, P < 0.001). Higher levels of sTNF-R in the sera of HAM patients were detected as compared with those of either controls (P < 0.001) or non-HAM carriers (P < 0.001). Patients with HAM exhibited significantly higher CSF levels of sTNF-R than those with other neurological diseases (P < 0.0001). These results suggest that the detection of sTNF-R in the sera and CSF may predict disease progression. Availability of such a marker would be useful in monitoring disease activity.