Background: This study aims to evaluate the cost-effectiveness of using heat and moisture exchangers (HMEs) vs alternative stoma covers (ASCs) following laryngectomy in the United States. Methods: A cost-effectiveness and budget impact analysis were conducted including uncertainty analyses using real-world survey data with pulmonary events and productivity loss. Results: HME use was more effective and less costly compared with ASCs. Quality-adjusted life years were slightly higher for HME-users. Total costs per patient (lifetime) were $59 362 (HME) and $102 416 (ASC). Pulmonary events and productivity loss occurred more frequently in the ASC-users. Annual budget savings were up to $40 183 593. Costs per pulmonary event averted were $3770. Conclusions: HME utilization in laryngectomy patients was cost-effective. Reimbursement of HME devices is thus recommended. Utilities may be underestimated due to the generic utility instrument used and sample size. Therefore, we recommend development of a disease-specific utility tool to incorporate in future analyses.