Prior to the development of ketoconazole, the treatment of systemic histoplasmosis and blastomycosis was limited to AMB. The convenience of oral dosing, combined with avoidance of the significant toxicities associated with AMB, make ketoconazole an attractive alternative for the treatment of selected forms of histoplasmosis and blastomycosis. Although high-dose (800 mg/day) ketoconazole is generally more effective than low-dose (400 mg/day), therapy should be initiated at the lower dose due to significantly more adverse effects at higher doses; the daily dose should be increased in patients with progressive disease. Caution should be exercised when ketoconazole is used to treat patients with GU tract disease and in patients with naturally occurring or pharmacologically induced achlorhydria. Thus, AMB remains the drug of choice for difficult to treat cases of histoplasmosis and blastomycosis; however, recent studies have established ketoconazole as the drug of choice in immunocompetent patients with non-life-threatening, non-meningeal H capsulatum and B dematitidis disease.