Topical methylglyoxal bis(guanylhydrazone) (MGBG) and alpha-difluoromethylornithine (DFMO) individually have been shown to produce partial clinical improvement in psoriasis. In an effort to further enhance therapeutic activity, studies were designed to optimize percutaneous penetraton of DFMO in vitro and to determine the effects of the combination of DFMO and MGBG on DNA synthesis and polyamine levels in hairless mouse skin. MGBG was shown to be more effective than DFMO in inhibiting DNA synthesis in vitro and in vivo. Maximum in vitro percutaneous penetration of DFMO (5%) was obtained in Vehicle N containing 10% Azone (297 micrograms/h/cm2). Topical administration of the combination of 5% DFMO and 0.1% MGBG in this vehicle produced a greater inhibition of DNA synthesis and depletion of polyamine levels than either drug individually. The simultaneous topical administration of DFMO and MGBG, allowing the use of lower concentrations of the more toxic MGBG, may be useful for therapy of psoriasis and other cutaneous disorders associated with abnormalities in polyamine metabolism.