Brucellosis, a zoonosis with worldwide distribution, is a systemic infection and still an important public health problem in Turkey. The best antimicrobial combination and schedule for the treatment of brucellosis with spondylitis has not yet been clearly determined. In a prospective and randomized study, we compared the efficacy of five antimicrobial regimens for treatment of 102 patients with lumbar brucellar spondylitis. Patients were randomly assigned to receive antimicrobial combination therapy. Twenty patients received streptomycin 1 g/day intramuscularly for 15 days and tetracycline-HCl, 500 mg every 6 h orally for 45 days (ST), 21 patients received streptomycin 1 g/day i.m. for 15 days and doxycycline 100 mg every 12 h orally for 45 days (SD), 20 patients received doxycycline 100 mg every 12 h orally for 45 days and rifampicin 15 mg/kg per day in a single morning dose orally for 45 days (DR), 19 patients received ofloxacin, 200 mg every 12 h orally for 45 days and rifampicin 15 mg/kg per day in a single morning dose orally for 45 days (OR), and 22 patients received streptomycin 1 g/day i.m. for 15 days and doxycycline 100 mg every 12 h orally for 45 days plus rifampicin 15 mg/kg per day in a single morning dose orally for 45 days (SDR). Initial therapeutic failure occurred in 2 patients (10%) in the ST regimen group, 4 patients (19%) in the SD group, 3 patients (15%) in the DR group and 5 patients (26%) in the OR regimen. In addition, 2 patients (10%) in the DR group and 5 patients (26%) in the OR regimen relapsed during the follow-up period. There was no relapse in any patients in the ST, SD, and SDR groups. The response rates were 90% in the ST and 81% in the SD groups. In contrast, there was a maximum good response (100%) and no relapse in the SDR group. In conclusion, a combination of doxycycline, streptomycin, and rifampicin can be recommended as therapy for brucellar spondylitis and to reduce relapse rates.