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To evaluate the efficacy and anti-inflammatory activity of systemic linoleic (LA) and γ-linolenic acid (GLA), which decrease chronic inflammation in rheumatoid arthritis, on the ocular surface of patients with keratoconjunctivitis sicca.In a randomized clinical trial, 26 patients with aqueous-deficient keratoconjunctivitis sicca were consecutively selected from patients presenting to Department of Neurosciences, Ophthalmology and Genetics, University of Genoa. The diagnosis was based on dry eye symptom survey score, Schirmer-1 test values, positive vital staining with lissamine green, and fluorescein break-up time (FBUT). All patients had ocular surface inflammation based on HLA-DR expression, a major histocompatibility class II antigen, on epithelial bulbar conjunctiva samples. The subjects were randomly divided into two groups of 13 patients each. The study group received tablets containing LA (28.5 mg) and GLA (15 mg) twice daily for 45 days and used tears; the control group received a tear substitute and a placebo tablet for 45 days.Statistically significant changes in symptoms (p < 0.005), lissamine green staining (p < 0.005), and ocular surface inflammation (p < 0.05) occurred in the study group compared with controls. HLA-DR expression varied from 58.5 ± 14.1% positive conjunctival cells to 41.3 ± 18.9% in the treated group and from 61.4 ± 21.9% to 58.0 ± 13.3% in the controls. No statistically significant difference between groups was found for FBUT and the Schirmer-1 test.Therapy with LA and GLA and tear substitutes reduces ocular surface inflammation and improves dry eye symptoms. Long-term studies are needed to confirm the role of this new therapy for keratoconjunctivitis sicca.