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Purpose: To compare dry eye symptoms and signs in a group of patients with Sjögren’s syndrome (SS), before and after the start of biological therapy for active systemic disease. Methods: Observational longitudinal retrospective study, including adult patients with a previous diagnosis of primary or secondary SS. Ocular Surface Disease Index (OSDI) test, tear breakup time (TBUT), and Schirmer test where registered before and after at least 1 year of use of biological therapy. Results: One hundred and nineteen patients were included, 83 (69.7%) females and 36 (30.3%) males, average age was 62.2 years, and the average time of use of biologics was 3.6 years. The main biologic agents used were adalimumab (22.7%), infliximab (20.2%), rituximab (16.0%), etanercept (13.4%), and abatacept (7.6%). After the implementation of biologic therapy, the percentage of patients with deficient and severely deficient Schirmer’s test decreased from 64.7% to 60.5% and from 18.5% to 11.8%, respectively, whereas adequate test increased from 16.8% to 27.7%. Deficient TBUT decreased from 74.8% to 63.0%. In OSDI evaluation, the percentage of asymptomatic patients increased from 3.4% to 18.5%, and severe symptoms decreased from 26.9% to 9.2%. Individual therapy analysis failed to find significative changes in terms of percentage variation and Cohen’s kappa for objective variables; however, substantial changes were observed in the OSDI test, particularly in patients treated with infliximab, rituximab, and abatacept. Conclusion: Use of biologics in SS remains restricted to patients with systemic active disease; however, a possible effect on dry eye symptoms arises as a secondary outcome, which could positively impact quality of life.