To study the pathophysiology of tick-borne encephalitis (TBE), the kinetics of neopterin and beta 2 microglobulin (beta 2M) production were measured in sequential, cerebrospinal fluid (CSF) and serum samples in 133 patients with aseptic meningoencephalitis (TBE, n = 72; non-TBE, n = 61). Intrathecal production of neopterin was demonstrable in all patients. Neopterin levels in CSF were elevated already at day 2: geometric mean value in TBE 36 nmol/l (range 1-253), in the non-TBE group 29 nmol/l (0.2-96). At day 9 and week 6 the neopterin level was significantly higher in TBE (86 (19-725) and 17 (4-122) nmol/l) than in non-TBE (28 (5-109) and 3 (0.2-58) nmol/l) (p < 0.001). After 1 year CSF levels were within the normal range. The beta 2M response in CSF followed the pattern of neopterin. The intensity and duration of neopterin and beta 2M was not correlated to the clinical course. Neopterin seems to be a more sensitive indicator of intrathecal T-cell response and inflammatory reaction than beta 2M. The results indicate that a long-lasting strong inflammatory reaction is of pathophysiological significance in TBE.