Numerous evidences support the pathogenesis that M. pneumoniae pneumonia is associated with cell-mediated immune reaction. We report 2 cases of severe M. pneumoniae pneumonia in previously healthy sisters, who were both admitted during an epidemic of M.pneumoniae pneumonia. The elder sister, who was 16 years old, was admitted with M. pneumoniae pneumonia. She showed no response to treatment with clarithromycin and levofloxacin, and eventually progressed to severe ARDS, requiring mechanical ventilation. After treatment with hydrocortisone (200 mg/day), there were rapid improvements in clinical manifestations and chest radiographic findings. The younger sister, who was 14 years old, was admitted 10 days later, presenting with fever but no pneumonic lesions on chest radiograph. Just like her sister, the infection showed no response to clarithromycin. Fever persisted and pneumonic consolidation with mild pleural effusion was noticed in the left lower lobe on the 5th hospital-day. After treatment with oral prednisolone (1 mg/kg), she showed rapid defervescence and on the 8th hospital day, no pneumonic lesions were detectable on chest radiograph. Given the fact that the pathogenesis of pneumonia and extrapulmonary manifestations in M. pneumoniae infection is immune-mediated, an immunosuppressive therapy would be validated for selected patients with M. pneumoniae infections.