Objectives To determine whether patients with primary Sjögren's syndrome (SS), diagnosed according to San Diego criteria, had improvement in their laboratory or clinical features during treatment with hydroxychloroquine (6–7 mg/kg/day) for at least two years., Methods: The study population included 50 consecutive patients with primary SS who were diagnosed according to San Diego criteria, and in whom hydroxychloroquine was suggested as treatment. This group included 10 patients who were early dropouts (side effects or desire not to take antimalarial drugs) and 40 patients who received drugs for at least two years (range 24-48 months). In a subset of SS patients, values for ESR (westergren) and quantitative immunoglobulins were available for comparison. Improvement with therapy was defined as: (a) ≥20% improvement in variables of tear flow (Schirmer's test I) or corneal integrity (rose Bengal): (b) ≥20% salivary function (flow rate); and (c) improvement in at least two of the following measures: physicians assessment of global disease activity by ≥ 20%, patient assessment of improvement in pain or fatigue by ≥20%, and ESR improved by ≥20mm/ hr. Results In a retrospective study of SS patients who completed the trial, a significant improvement was noted in ocular symptoms (pain and dryness) in patients (55 and 57%) and improved corneal integrity (rose Bengal straining) in 53% of patients. The Schirmer's test was improved by ≥ 2 mm/5 minutes in 50% in patients. Improvement was noted in oral symptoms (pain and dryness) in patients (57 and 60%) and salivary flow rate was increased in 82% of patients. In a subset of SS patients evaluated, the ESR improved by ≥20mm/hr in 17/32 patients (53%) and quantitative IgG level by ≥20% in 8/13 patients (61%). Physician global assessment of overall patient status and patient assessment of overall status indicated improvement in over 62% of patients. Conclusion In a retrospective study of patients fulfilling San Diego Criteria for SS, we found: (a) sustained improvement of local symptoms (painful eyes, painful mouth) and improvement of systemic manifestations (arthralgias and myalgias) after treatment with hydroxychloroquine 6-7 mg/kg/day over mean three-year follow-up; (b) laboratory analysis showed a significant improvement in their ESR and their quantitative IgG levels; (c) no significant late toxicity was observed in this study cohort. A prospective study of hydroxychloroquine in patients fulfilling San Diego criteria for SS is indicated.