Recent studies point out a probable role of streptococcal antigens in the pathogenesis of Behçet's disease (BD). This has led to the proposal of benzathine penicillin as a therapeutic modality in BD. A prospective study was conducted to compare the efficacy of colchicine and colchicine + benzathine penicillin treatments on mucocutaneous manifestations of BD. 60 patients (group I) were given colchicine alone and 94 (group II) were given colchicine + benzathine penicillin. Frequency, number, duration and severity of oral aphthous ulcers, genital ulcers and erythema nodosum were determined before and after treatment. In group I, all parameters of oral ulcers and the frequency and healing time of genital ulcers and erythema nodosum decreased significantly. In group II, all parameters of oral aphthous ulcers, genital ulcers and erythema nodosum were significantly improved. When treatment results in the two groups were compared, the decrements in the frequency and duration of oral ulcers and erythema nodosum and the frequency of genital ulcers were significantly greater in group II than in group I (p < 0.05). We conclude that prophylactic benzathine penicillin combined with colchicine is more effective in controlling mucocutaneous manifestations of BD than colchicine alone.