Clarithromycin (CAM), a 14-membered ring macrolide, has anti-inflammatory and immunomodulatory actions and antiviral effects in seasonal influenza virus infection. We examined the prophylactic and therapeutic efficacy of CAM against H5N1 highly pathogenic and H7N9 low pathogenic avian influenza virus infections in cynomolgus monkeys. CAM suppressed H5N1 virus-induced severe signs of disease in the treated monkeys and inhibited virus propagation in tracheal samples and the production of inflammatory cytokines in the lungs of monkeys infected with H5N1 and H7N9 viruses. The prophylactic administration of CAM showed more suppressive effects on clinical signs of disease and viral titers than did therapeutic administration. Thus, since administration of CAM alone showed a tendency to ameliorate clinical sings and to reduce levels of inflammatory cytokines, the macrolides are expected to have effects in combination with the other antiviral drugs on the prophylactic and treatment of patients with severe avian influenza virus infection, which should be further investigated.