Rationale: Laryngopharyngeal reflux affects up to 20% of western populations. Although individual morbidity is usually moderate, treatment costs are high and there are associations with other diseases, including laryngeal cancer. To date, there have been no studies of the mucosal immune response to this common inflammatory disease. Objectives: To determine the mucosal immune response to laryngopharyngeal reflux. Methods: We performed a prospective immunological study of laryngeal biopsies from patients with laryngopharyngeal reflux and controls (n=12, 11), and of primary laryngeal epithelial cells in vitro. Measurements: Quantitative multiple colour immunofluorescence, using antibodies for lymphocytes (CD4, CD8, CD3, CD79, CD161), granulocytes (CD68, EMBP), monocytic cells (CD68, MHC II) and classical and nonclassical MHC (I, II, ₂m, CD1d). Uni-and multi-variate analysis and co-localisation measurements were applied. Main results: There was an increase in percentage area of mucosal CD8⁺ cells in the epithelium (p<0.005), whereas other leukocyte and granulocyte antigens were unchanged. Although epithelial MHC Class I and II expression was unchanged by reflux, expression of the nonclassical MHC molecule CD1d increased (p<0.05 luminal layers). In vitro, laryngeal epithelial cells constitutively expressed CD1d. CD1d and MHC I expression were inversely related in all subjects, in a pattern which appears unique to the upper airway. Co-localisation of NKT cells with CD1d increased in patients (p<0.01). Conclusions: These data indicate a role for the CD1d-NKT cell axis in response to laryngopharyngeal reflux in man. This represents a useful target for novel diagnostics and treatments in this common condition.