Multiple endocrine neoplasia type 2B (MEN2B) is a rare cancer predisposition syndrome resulting from an autosomal-dominant germline mutation of the RET proto-oncogene. No prior studies have investigated pulmonary function in patients with MEN2B. This study characterized the pulmonary function of patients with MEN2B. This is a retrospective analysis of pulmonary function tests (PFTs) and chest imaging of patients enrolled in the Natural History Study of Children and Adults with MEN2A or MEN2B at the National Institutes of Health. Thirty-six patients with MEN2B (18 males, 18 females) were selected based on the availability of PFTs; 27 patients underwent at least 2 PFTs and imaging studies. Diffusion abnormalities were observed in 94% (33/35) of the patients, with 63% (22/35) having moderate to severe defects. A declining trend in diffusion capacity was seen over time, with an estimated slope of -2.9% per year (P = 0.0001). Restrictive and obstructive abnormalities were observed in 57% (20/35) and 39% (14/36), respectively. Computed tomography imaging revealed pulmonary thin-walled cavities (lung cysts) in 28% (9/32) of patients and metastatic lung disease in 34% (11/32) of patients; patients with metastatic lung lesions also tended to have thin-walled cavities (P = 0.035). This study characterized pulmonary function within a MEN2B cohort. Diffusion, restrictive, and obstructive abnormalities were evident, and lung cysts were present in 28% of patients. Further research is required to determine the mechanism of the atypical pulmonary features observed in this cohort. Published by Oxford University Press on behalf of the Endocrine Society 2020.