The structure of the oral mucosa is now well characterised, although studies on oral epithelial cell function have received less attention. The aims of this study were to see whether endocytosis could be demonstrated in cells from oral smears and, if so, to assess the effect of chronic high alcohol intake on such uptake. Buccal mucosal smears were collected from 135 patients (91 non- or social drinkers, and 44 patients with harmful alcohol use). Name, age, sex, and alcohol history (for alcohol problem patients) were recorded. Cell suspensions were incubated in a solution of bovine serum albumin (BSA)-coated fluorescently labelled latex microspheres (0.02 µm diameter) in Ham's F-10 culture medium for 1 h at 37°C as a marker of fluid phase endocytosis. Uptake of microspheres was confirmed by confocal microscopy, and mean endocytosed fluorescence levels determined by flow cytometry. A repeat smear from 11 of the alcohol patients was taken 9-14 days later. Endocytosis was significantly reduced in both male (P <0.01) and female (P <0.01) alcohol problem patients compared to controls. Units of alcohol consumed and cigarettes smoked per day did not show a dose-response correlation with endocytosis in the alcohol problem patients. Apparent abstinence from alcohol had no further effect on endocytic uptake at days 9- 14. This study shows that normal oral squamous cells removed as buccal smears readily endocytose fluorescent microspheres and that this capacity can be affected by alcohol. Chronic high alcohol intake would appear to down regulate endocytosis in buccal cells even up to 14 days of abstinence. This may have implications for the pathogenesis of oral mucosal disorders in long- term users.