Quinolones have been reported to be active against Brucella species in vitro. In this prospective randomized study, the efficacy and safety of the combination of ofloxacin plus rifampin were compared with the efficacy and safety of doxycycline plus rifampin, both combinations administered for a 6-week period in treatment of brucellosis. Sixty-one patients were enrolled in the study, and 49 had blood or bone marrow cultures positive for Brucella melitensis. Thirty patients received 200 mg of doxycycline plus 600 mg of rifampin once daily, and 31 patients were treated with 400 mg of ofloxacin plus 600 mg of rifampin once daily for 6 weeks. Nine patients in each group had complications of the disease. There was one therapeutic failure in the ofloxacin-rifampin treatment group, and one patient from each group relapsed (3.3% of those in the doxycycline-rifampin treatment group versus 3.2% of those in the ofloxacin-rifampin treatment group). Gastric discomfort was the major side effect observed in 13 patients (43.3%) who received doxycycline plus rifampin, whereas only 2 patients (6.5%) treated with ofloxacin plus rifampin complained of gastric irritation. These results suggest that the combination of ofloxacin plus rifampin administered for 6 weeks is as effective as doxycycline plus rifampin given for the same period, regardless of the presence of complications of the disease.