Background Recurrent respiratory papillomatosis (RRP) or laryngeal papillomatosis is a disease caused by papillomavirus infection. Methods In this phase I/II clinical trial, we evaluated the efficacy of the modified vaccinia Ankara (MVA) E2 virus in the treatment of RRP. Twenty‐nine patients (18 female and 11 male) underwent injection of MVA E2 directly into the borders of the vocal cords where lesions were seen and were monitored by direct laryngoscopy. The immune response was assessed by the determination of CD3+, CD4+, and CD8+ lymphocytes counts. The presence of papillomavirus was determined by polymerase chain reaction analysis. Results Lesions were completely eliminated in 13 patients (44.8%). In 16 patients (55.2%), lesions recurred between 6 and 18 months after treatment; these patients received a second round of treatment with MVA E2, and they are not seen with new recurrences. Conclusion The MVA E2 vaccine has excellent potential for generating complete regression of RRP lesions.