Systemic therapy of encephalitis with human interferon-beta regularly causes fever up to more than 41 degrees C. Patients often developed hematological changes, nausea and tachycardia. Analyzing the temperature curves of 13 patients with repeated intrathecal, lumbar instillations of 1.0 x 10(6) IU natural IFN-beta, we found markedly less drug-associated fever. Mean temperature was maximal at 38.7 degrees C 12 h after instillation; individual temperature did not exceed 39.7 degrees C, and was elevated for less than 36 h. Day-time of application did not change these results. After the first IFN-beta instillations, the mean integral of temperature vs time was twice as high as after subsequent applications. One and a half days after intrathecal administration and from 39 degrees C on, fever is independent from lumbar IFN-beta. Lower dosage, a more than ten-fold reduction of costs and less interference led us to prefer intrathecal interferon-beta applications. Given the data presented, we cannot yet evaluate clinical efficacy of intrathecal IFN-beta.