The efficacy and tolerability of three different combination treatment regimens in human brucellosis were compared in 118 uncomplicated patients enrolled in a prospective study between May 1997 and December 2002. Brucellosis was diagnosed using standard clinical and microbiological findings. Patients with central nervous system involvement, spondylitis, endocarditis or children under 16 years of age were excluded from the study. Patients were randomly assigned to receive 400 mg of ofloxacin plus 600 mg of rifampicin (OR, n = 41), 200 mg of doxycycline plus 600 mg of rifampicin (DR, n = 45) or 1g intramuscularly streptomycin (administered for three weeks) plus 200 mg doxycycline (DS, n = 32) daily for 6 weeks. All patients were followed up at least 6 months after cessation of therapy. There was no statistical difference between the groups on relapse rates and clinical response to the treatment (P>0.05). Five patients in OR (12.8%), six patients in DR (14.3%) and three patients in DS groups (9.7%) suffered relapse. The side-effects were seen in eight (19.5%), 21 (46.7%) and eight (25.0%) patients of OR, DR and DS groups, respectively. The use of combination therapy of ofloxacin plus rifampicin for 6 weeks was found to be as effective as DR and DS. The side-effects of therapy in OR and DS groups was less severe than in the DR group.