Twelve men with louse-borne relapsing fever were treated with single doses of procaine penicillin plus aluminum monostearate (PAM) intramuscularly or of tetracycline intravenously. All patients experienced a definite Jarisch-Herxheimer-like reaction. Fever and spirochetemia were significantly prolonged and peak temperature was lower and occurred later in the PAM-treated group. Peak pulmonary ventilation, metabolic rate, and arterial PO2 were significantly higher in the tetracycline-treated group. Circulatory changes were similar in the two groups but were prolonged in the PAM-treated patients. Thus, tetracycline is recommended for treatment because it is more rapidly effective in eliminating Borrelia spirochetes and produces a reaction no more stressful physiologically than the one after PAM. There was no evidence of complement activation, and there was no change in immunoglobulin levels throughout the reaction. Immune complexes were detected in serum of five patients before treatment, but in fewer patients at the peak of the reaction and subsequently.