A 20-year-old man with no prior significant medical history developed fever, chest tightness, H1N1 influenza, Mycoplasma pneumoniae pneumonia, and right-sided massive spontaneous pneumothorax. Despite early closed chest drainage with precautions against reexpansion pulmonary edema (RPE), the patient developed RPE and refractory pneumothorax. Finally, thoracoscopic surgical intervention was required. The patient did not require invasive mechanical ventilation and made a full recovery after intensive care. Coinfection with H1N1 and Mycoplasma pneumoniae aggravates lung parenchymal damage, facilitates pneumothorax, prevents healing, and increases the risk of RPE. RPE is a rare but potentially fatal complication following pneumothorax drainage. Physicians should be especially vigilant in young patients with short disease duration and complex infections, emphasizing drainage strategies, monitoring, and early surgery.