We evaluated the efficacy of azithromycin therapy given as a single high dose or divided over 5 days for the treatment of mild experimental Mycoplasma pneumoniae pneumonia. Although both azithromycin regimens significantly reduced quantitative cultures, lung histopathology, and pulmonary cytokines and chemokines, there were no significant differences between the two regimens.It is unknown if antimycoplasmal therapy can be optimized utilizing high-dose azithromycin therapy. The purpose of the present study was to evaluate the microbiologic and immunologic efficacy of azithromycin therapy given as a single highdose compared with divided doses over 5 days in our murine Mycoplasma pneumoniae pneumonia model (6,7,10). We compared the activities of these two regimens on the clearance of M. pneumoniae from the respiratory tract and assessed their impact on the pulmonary immune response as measured by bronchoalveolar lavage cytokines and chemokines and by histologic inflammation.As previously described in full detail, 2-month-old female BALB/c mice (Charles River) were intranasally inoculated once (day 0) with 10 7 to 10 8 CFU of M. pneumoniae (ATCC 29342) in 50 l SP4 broth (4, 7, 10). Methoxyflurane, an inhaled anesthetic, was used for inoculum sedation. Animal guidelines were followed in accordance with the Institutional Animal Care and Research Advisory Committee. Azithromycin (Pfizer) for injection was dissolved in sterile water as per container instructions. Azithromycin was given 24 h after M. pneumoniae inoculation and administered subcutaneously at 50 mg/kg of body weight for only 1 day (dosage, 1 mg in 0.1 ml per mouse) or 10 mg/kg once daily for 5 days (dosage, 0.2 mg in 0.1 ml per mouse). The placebo group received sterile water for 5 days starting at 24 h after inoculation. We used 10 mg/kg as the conventional azithromycin dosage in this study as it has been used in other mouse studies and has been shown to be