The purpose of this randomized, controlled, masked study was to evaluate the effects of latanoprost 0.005% (Xalatan, Pharmacia and Upjohn, Milan, Italy) on the ocular surface in patients with ocular hypertension or primary open-angle glaucoma. The study group included 14 patients who underwent latanoprost 0.005% eye drops once a day in both eyes for 4 months. The control group underwent unpreserved substitute tears eye drops (Aquasalina, Bruschettini, Genoa, Italy) with the same posology and the same concentration of benzalkonium chloride (0.02%). Patients were controlled at 1, 3 and 4 months for symptoms, intraocular pressure, corneal sensitivity (Cochet-Bonnet test) and fluorescein staining. At the same control times, they underwent impression cytology and conjunctival brush cytology. Immunohistochemical techniques were used to detect HLA-DR expression in conjunctival cells. At each control, no significant statistical differences were found between the study and the control group, except for a higher expression of HLA-DR in the latanoprost group (p < 0.001). Since HLA-DR is a marker of ocular surface inflammation, this study suggests that a subclinical inflammatory reaction is present in the ocular surface of patients under latanoprost therapy. The pathway by which the inflammation is stimulated is yet unknown.