Diagnosis of central nervous system (CNS) involvement in human African trypanosomiasis is crucial in determination of therapy. Cerebrospinal fluid (CSF) and serum immunoglobulin concentrations, blood-CSF barrier dysfunction, pattern of intrathecal immunoglobulin synthesis, trypanosome-specific antibody synthesis, and CSF lactate concentrations were analyzed in 272 patients with Trypanosoma brucei gambiense infection. As part of the 2- or 3-class immune response, the predominant intrathecal IgM synthesis was the most sensitive (95%) marker for inflammation of the brain. We propose to replace the World Health Organization (WHO) criteria (white blood cell count >5 cells/microL and presence of trypanosomes in CSF) with a new approach for stage determination in trypanosomiasis: CNS involvement is diagnosed only in patients with >20 cells/microL or with intrathecal IgM synthesis, independent of the presence of trypanosomes in CSF. Compared with the use of these new criteria, the WHO criteria incorrectly classified 49 of 234 patients in the meningoencephalitic stage and 7 of 38 patients in the hemolymphatic disease stage. We also show that trypanosomiasis-related immunoglobulin patterns are of value in differential diagnosis.