Recurrent respiratory papillomatosis (RRP) can be difficult to manage. Symptoms are related to recurrent tracheobronchial papillomas and are usually treated with bronchoscopic removal. Other modalities are added when the papilloma burden becomes too great or recurrence is too frequent, but with limited efficacy. We report a patient with progressive RRP that had become refractory to available therapy. Because papillomas overexpress epidermal growth factor receptor, along with increased expression of cyclooxygenase-2 and prostaglandin E2, it was reasoned that a combination therapy of erlotinib and celecoxib would be effective in controlling papilloma growth. After institutional approval and informed patient consent, this combination was initiated. There was a striking improvement in the number and appearance of respiratory tract papillomas, with elimination of the need for repeated papilloma removal. Pretreatment and posttreatment images document this response, and the improvement has now been maintained for nearly 2 years with effective therapy.