Behçet disease is a chronic relapsing disease characterized by multiple signs and symptoms such as recurrent orogenital ulceration, eye involvement, skin manifestations, and other systemic involvement. Multiple therapeutic modalities have been used to treat Behçet disease. These agents act through different mechanisms and are associated with a variety of side effects. We performed a case-comparative study to evaluate efficacy of combined colchicine and benzathine penicillin in the treatment and prophylaxis of Behçet disease. Sixty-six patients who fulfilled the international study group criteria for diagnosis of Behçet disease were included. The patients were divided into three groups: group 1 (20 patients) received 1.2 Mu benzathine penicillin injection monthly; group 2 (21 patients) received two tablets of colchicine daily (each tablet contained 0.5 mg); and group 3 (25 patients) received both 1.2 Mu benzathine penicillin injection monthly and two tablets of colchicine daily. Each patient was followed up monthly for 5 months, 4 months on treatment and 1 additional month followup. The clinical manifestation index (CMI), the numerical sum of the clinical features, was calculated for each patient initially and then monthly. Pathergy test was performed for each patient monthly. The CMI was reduced by colchicine and benzathine penicillin treatment, and the reduction was highly significant. The reduction in the CMI remains satisfactory and good for 1 month after stopping the treatment. When each colchicine and benzathine Penicillin are used alone the index is also reduced significantly, but this reduction is much less than when both drugs are used together and there is also rapid and earlier relapse. Based on our findings, the combination of colchicine and benzathine penicillin appears to be of greater efficacy in the treatment of Behçet disease than the use of either drug alone.