© 2016, American Society for Microbiology. All Rights Reserved. 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 (Pnot 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 (PNS). 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 (PNS). 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.