An 18-year-old student with a history of asthma accidentally inhaled organic solvent during a class, with immediate cough and dyspnea that worsened over several hours. He presented in severe respiratory distress, with hypoxemia and marked pulmonary hyperinflation. Administration of inhaled bronchodilator was ineffective because of agitation, and the patient could not be positioned for chest physiotherapy to treat presumed widespread mucus plugging. High-frequency chest wall oscillation (HFCWO) in the sitting position initially caused increased distress but was subsequently tolerated when noninvasive positive-pressure ventilation (NPPV) via nasal mask was initiated. Almost immediately, the patient began expectorating bronchial mucus casts, with concomitant clinical improvement. Endotracheal intubation was avoided, and with aggressive pharmacologic treatment for acute severe asthma and continuation of intermittent HFCWO-NPPV, the patient made a full recovery over the next several days. This case suggests that the combination of HFCWO and NPPV may be helpful in the presence of mucus plugging as a complication of acute inhalation injury or acute severe asthma.