OBJECTIVE This study aimed at evaluating from a morphological point of view the effects of alendronate (ALN), a widely used nitrogen-containing bisphosphonate for the chronic treatment of osteoporosis, on the oral epithelium of healthy keratinized human oral mucosa. Bisphosphonate-related osteonecrosis of the jaw is a well-known severe consequence, but the effects during chronic therapy on the oral soft tissues are still matter of debate. MATERIALS AND METHODS Six women over 60 year-old undergoing treatment of osteoporosis with 70 mg per week of oral ALN (lasting at least 2 years) were recruited and compared with a gender and age-matched group (n = 6). Proliferation, apoptosis, intercellular adhesion and terminal differentiation (TD) were investigated by immunofluorescence. In parallel, ultrastructural analysis was carried out. RESULTS By immunofluorescence, a statistically significant decrease in keratinocyte proliferation was detected in the oral epithelium of the ALN group without any sign of apoptosis, but accompanied by a reduction in desmoglein 1 and keratin 10 expressions. In the uppermost layers of the oral epithelium of the ALN group, thin desmosomes were visible by transmission electron microscopy. CONCLUSION Our results show that epithelial adhesion, TD and proliferation are affected by ALN therapeutic doses in clinically healthy human oral mucosa.