Human African trypanosomiasis treatment is stage dependent, but the tests used for staging are controversial. Central nervous system involvement and its relationship with suramin treatment failure were assessed in 60 patients with parasitologically confirmed hemolymphatic-stage Trypanosoma brucei gambiense infection (white blood cell count of <or=5/microl and no trypanosomes in the cerebrospinal fluid [CSF]). The prognostic value of CSF interleukin-10, immunoglobulin M (IgM; as determined by nephelometry and the point-of-care LATEX/IgM test), total protein, and trypanosome-specific antibody was assessed. The IgM and interleukin-10 levels in serum were measured; and the presence of neurological signs, intrathecal IgM synthesis, and blood-CSF barrier dysfunction was determined. After suramin treatment, 14 of 60 patients had relapses (23%). Relapses were significantly correlated with intrathecal IgM synthesis (odds ratio [OR], 46; 95% confidence interval [CI], 8 to 260), a CSF IgM concentration of >or=1.9 mg/liter (OR, 11.7; 95% CI, 2.7 to 50), a CSF end titer by the LATEX/IgM assay of >or=2 (OR, 10.4; 95% CI, 2.5 to 44), and a CSF interleukin-10 concentration of >10 pg/ml (OR, 5; 95% CI, 1.3 to 20). The sensitivities of these markers for treatment failure ranged from 43 to 79%, and the specificities ranged from 74 to 93%. The results show that T. brucei gambiense-infected patients who have signs of neuroinflammation in CSF and who are treated with drugs recommended for use at the hemolymphatic stage are at risk of treatment failure. This highlights the need for the development and the evaluation of accurate point-of-care tests for the staging of human African trypanosomiasis.