Gastroesophageal reflux disease (GERD) can be associated with ear, nose, and throat signs and symptoms, a condition often referred to as laryngopharyngeal reflux (LPR). However, the morphologic alterations of laryngeal mucosa associated with LPR are currently poorly understood. Since the dilation of intercellular spaces (DIS) between squamous epithelial cells is considered a morphologic marker of acid damage to esophageal mucosa in GERD, we evaluated whether similar changes can be detected in the laryngeal epithelium of patients affected by LPR. The study group included 15 patients affected by LPR and 7 normal controls, who underwent laryngeal biopsies at the interarytenoid area. Specimens were routinely processed for light microscopic and ultrastructural examination. The intercellular spaces were measured in electron microscopy images using a computer assisted morphometric system. Ultrastructural analysis demonstrated an irregular intercellular space dilation in specimens from the group of patients with LPR. Another ultrastructural abnormality observed in a minority of patients was the presence of numerous cytoplasmic vacuoles. Computer assisted morphometric analysis demonstrated that the intercellular space between squamous cells was significantly wider in patients with LPR than in control subjects (411.7 nm +/- 188.6 SD vs. 155.8 nm +/- 56.4 SD, P = 0.003). These data indicate that ultrastructural evidence of DIS of epithelial cells may be a morphologic marker of acid reflux, as already described in esophageal mucosa. If this result will be confirmed in larger series it may provide a useful diagnostic tool for the identification of LPR.