A total of 389 patients with late-stage Trypanosoma brucei gambiense trypanosomiasis were enrolled in a randomized controlled trial comparing the efficacy and toxicity of three regimens of melarsoprol: regimen A, 3.6 mg/kg (max. 180 mg) for all i.v. injections, given as three series of three injections separated by 1-week intervals; regimen B, 10 consecutive daily i.v. injections of 2.16 mg/kg; or regimen C, three series of three i.v. injections separated by 1-week intervals, but with graded dosing (1.8, 2.16, 2.52, 2.52, 2.88, 3.24, then 3.6 mg/kg for the last three injections). After treatment, patients were followed with half-yearly lumbar punctures for 2 years. During treatment, convulsions were significantly more common in patients allocated to the graded dosing regimen (7/70 [10.0%] vs. 11/319 [3.4%], P = 0.03). The 2-year probability of relapse was 5.4%, 7.4% and 25.0% for regimens A, B and C respectively (P < 0.001). The new regimen of 10 daily injections of melarsoprol was as effective and had the same toxicity as the traditional regimen of three series of three injections at the full dose. Graded dosing, which was associated with a much lower efficacy and more frequent convulsions, should be abandoned.