The classic antibiotic treatment for Mediterranean spotted fever (MSF) is based on tetracyclines or chloramphenicol, but chloramphenicol's bone marrow toxicity makes tetracyclines the treatment of choice. However, it is convenient to have alternatives available for patients who are allergic to tetracyclines, pregnant women, and children <8 years old. We conducted a randomized clinical trial to compare clarithromycin with doxycycline or josamycin in the treatment of MSF. Forty patients were evaluated (23 male; mean age, 39.87 years); 13 patients were aged <14 years. Seventeen patients received clarithromycin, and 23 received doxycycline or josamycin. The interval between the onset of symptoms and the start of treatment was 4.04 ؎ 1.70 days in the clarithromycin group versus 4.11 ؎ 1.60 days in the doxycycline/josamycin group (P ‫؍‬ not significant [NS]). Time to the disappearance of fever after treatment was 2.67 ؎ 1.55 days in the clarithromycin group versus 2.22 ؎ 1.35 days in the doxycycline/ josamycin (P ‫؍‬ NS). The symptoms had disappeared at 4.70 ؎ 2.25 days in the clarithromycin group versus at 4.75 ؎ 3.08 days in the doxycycline/josamycin (P ‫؍‬ NS). There were no adverse reactions to treatment or relapses in either group. In conclusion, clarithromycin is a good alternative to doxycycline or josamycin in the treatment of MSF. Mediterranean spotted fever (MSF) is a spotted fever group rickettsiosis. Caused by Rickettsia conorii, MSF is endemic in the Mediterranean area. Clinically, MSF is characterized by fever, exanthema, and the inoculation eschar known as tache noire. MSF affects people of both sexes and all ages (1-3).Antibiotic therapy helps prevent progression to severe disease and the associated mortality (4). Classic antibiotic therapy consists of tetracyclines or chloramphenicol, although the use of chloramphenicol in developed countries is limited by its bone marrow toxicity (5).Both in vitro and in vivo studies have shown that doxycycline is highly efficacious in this group of rickettsiosis. Even short-course treatments with doxycycline are highly effective (6). Nevertheless, it would be useful to have alternative treatments for patients allergic to tetracyclines, pregnant women, and children Ͻ8 years old.In vitro studies have shown that rifampin, the fluoroquinolones, and some macrolides have good activity against R. conorii (7, 8); however, of these, only josamycin has proven efficacy in vivo (9). Although josamycin has been commercially available for years in some countries (e.g., France, Switzerland, Austria, Italy, South Africa, and Spain), it is unavailable in many others. Thus, it would be useful to have another antibiotic that can be obtained in most countries to treat MSF.Several studies showed that clarithromycin and its metabolite 14-hydroxyclarithromycin have excellent in vitro activity against R. conorii and Rickettsia rickettsii (10-12), and these results were confirmed in clinical studies, where clarithromycin was efficacious and safe in treating children with spotted fever group...