We conducted an open-label randomized controlled trial to compare the efficacy and safety of clarithromycin (15/mg/kg/day in 2 divided doses for 7 days) with those of azithromycin (10 mg/kg/day in 1 dose for 3 days) in the treatment of children with Mediterranean spotted fever. Until now, there has not been a gold-standard therapy for this rickettsial disease in children. Eighty-seven children were randomized to receive 1 of the 2 drugs. The mean time to defervescence (+/- standard deviation) was 46.2+/-36.4 h in the clarithromycin group and 39.3+/-31.3 h in the azithromycin group. These differences were not statistically significant and both drugs were equally well-tolerated. Clarithromycin and azithromycin could be acceptable therapeutic alternatives to chloramphenicol and tetracyclines for children aged < or =8 years with Mediterranean spotted fever. Azithromycin, because it has a long half-life, offers the advantages of administration in a single daily dose and a shorter duration of therapy, which could increase compliance in children.