A clinical trial was conducted in order to evaluate the efficacy of procaine penicillin and tetracycline, respectively, in the treatment of louse-borne relapsing fever. 184 patients (160 men, 24 women) admitted to the Gondar hospital during the rainy season 1992 were assigned to 1 of 4 treatment groups: procaine penicillin 100,000 (PP100), 200,000 (PP200) or 400,000 (PP400) international units (IU) intramuscularly (i.m.), or tetracycline 250 mg per os (TTC, p.o.). All drugs were given as single doses. The overall case fatality rate was 3.3%. Frequency of relapses, Jarisch-Herxheimer-like reactions (JHR) and deaths were significantly different between patients treated with TTC and those treated with PP100. Relapses occurred most often in the group receiving the lowest dose of penicillin (46%), and decreased with increasing dosage of penicillin; none of the patients treated with TTC had a relapse. Occurrence of JHR showed the opposite pattern: whilst 2 (5%) patients treated with PP100 developed a JHR, 16 (29%) in the PP200 group, 10 (31%) in the PP400 group, and 27 (47%) in the TTC group developed a JHR. As mortality is linked to severe JHR, and most relapses are clinically mild and easily treated, these results speak in favour of using low-dose penicillin to initiate the treatment of relapsing fever.