The activities of therapeutic regimens with azithromycin (AZI) and doxycycline combined with streptomycin (DOX-SM) were compared in Brucella melitensis infected mice. In a chronic model, AZI given over 10, 14 or 21 consecutive days (50 mg/kg/24 h) significantly reduced the infection (1.3-1.6 logs, day 48 post-infection). However, the effectiveness of DOX (21 days, 50 mg/kg/12 h) was higher than AZI (3.4 logs of reduction, day 48 post-infection). Besides, when DOX was administered for 45 days, it "cured" all the animals from day 78. Similar results were obtained in an acute model infection. One single dose of DOX or DOX-SM, starting one day after lethal challenge, was able to protect 83% of the mice. In contrast, only 25% of the mice treated with AZI (50-200 mg/Kg) survived the challenge. Our findings demonstrate that AZI, in contrast to DOX-SM, does not cure experimental brucellosis.