Dexamethasone-immunosuppressed rats infected with Cryptosporidium parvum were used to assess the macrolides azithromycin and spiramycin for anticryptosporidial activity. Azithromycin consistently prevented ileal infection, while spiramycin was ineffective. The anticryptosporidial activity of azithromycin was dose-related, 200 mg/kg/day being the minimum dose that prevented infection. Therapeutically, azithromycin eliminated an established overt infection of the small intestine in immunosuppressed rats, but the infection recurred after azithromycin treatment was stopped. These findings suggest that azithromycin is a potentially useful anticryptosporidial agent and that long-term continuous administration may be necessary to treat cryptosporidiosis in the immunocompromised host.