Esophageal papillomas are rare. Both local irritation as by gastroesophageal reflux and infections with human papillomavirus (HPV) have been implicated as etiological factors. We here describe a 28-year-old female patient with massive esophageal papillomatosis. The clinical course has been mild, with signs of regression after a 3 1/2-year observation period. An extensive evaluation showed no predisposing diseases, and test results for HPV using sensitive methods were negative despite histological features suggesting virus infection and concomitant pharyngeal papillomas that are known to be caused by HPV. This case underlines the incomplete understanding of the etiology of this disease.