Pulmonary toxicity induced by trimethoprim-sulfamethoxazole (TMP-SMX) has been described, although the disease process is poorly understood. We report 5 previously healthy adolescent patients who developed acute respiratory failure while taking TMP-SMX. Four of the 5 adolescents required extracorporeal membrane oxygenation support, and 2 of the teenagers died. All children required a tracheostomy, and all cases were complicated by pneumothoraces and pneumomediastinum. The majority of children were prescribed TMP-SMX for the treatment of acne vulgaris.