Purpose: To review the clinical, radiologic, serologic, histopathologic, immunohistochemical, and molecular genetic features of patients having Sjgren’s syndrome (SS) with lacrimal gland enlargement. Design: Retrospective case series review. Participants: Fourteen patients histopathologically diagnosed with SS with lacrimal enlargement. Twenty-three age-and gender-matched controlswere used for comparison on radiologic analysis. Methods: Clinical and serologic data were determined directly or by chart review. Computed tomography images from patients were compared with those from the control group. Histopathologic sections were reviewed and graded using the Chisholm-Mason scale, and quantitative immunohistochemical analysis was applied. Main Outcome Measures: Clinically, patients were assessed for age, gender, onset, symptoms and signs, systemic features, treatment, and outcome. Existing histologic specimens were reviewed according to the Chisholm-Mason scale, and then the percentages of plasma cells containing immunoglobulin (Ig) A, IgG, and IgM were determined. Imagingwas assessed for lacrimal gland thickness, prolapse, density, and margin contour; extraocular muscle size; orbital tissue displacement; and proptosis. Results: Clinical and histopathological data fulfilled the revised American-European criteria for primary SS in 79%of patients. Compared with other large series of primary SS patients, similaritieswere found with age, xerophthalmia, parotidomegaly, and articular involvement. Differences included a lower incidence of autoantibodies, xerostomia, and extraglandular features and a higher male-to female ratio. In almost all patients (93%), the percentage of plasma cells positive for IgA was less than 70%, consistentwith SS. Compared with controls, the lacrimal glands were enlarged significantly (P < 0.0001) and prolapsed (P < 0.001). Involved glands had blurred margins (P < 0.007), caused displacement of adjacent tissues (P=0.03), and were associated with hyperdense fat (P=0.007). Lymphocytic infiltration of orbital fatwas present in all patients for whom fat biopsy results were available. Three patients had monoclonal infiltrates, and 1 patient experienced subsequent extranodalmarginal zone lymphomaof mucosa-associated lymphoid tissue type, 4 years after presentation. Conclusions: The criteria used to diagnose primary SS are controversial, but both diagnostic and quantitative immunohistochemical criteria suggest that these patients, with lacrimal gland enlargement resulting from lymphocytic infiltration, represent a new subtype of primary SS. This is clinically important in view of the increased risk of lymphoma associated with SS, compared with idiopathic nonspecific lacrimal inflammation. Purpose: To review the clinical, radiologic, serologic, histopathologic, immunohistochemical, and molecular genetic features of patients with Sjögren’s syndrome (SS) with lacrimal gland enlargement. Design: Retrospective case series review. Participants: Fourteen patients histopathologically diagnosed with SS with Twenty-three age-and gender-matched controlswere used for comparison on radiologic analysis. Methods: Clinical and serologic data were determined directly or by chart review. Computed tomography images from patients were compared with those from the control group. Histopathologic sections were reviewed and graded using the Chisholm-Mason scale, and quantitative immunohistochemical analysis was applied. Main Outcome Measures: Clinically, patients were assessed for age, gender, onset, symptoms and signs, systemic features, treatment, and outcome. reviewed according to the Chisholm-Mason scale, and then the percentag Results of Clinical and histopathological data: es of plasma cells containing immunoglobulin (Ig) A, IgG, and IgM were determined. Imaging was assessed for lacrimal gland thickness, prolapse, density, and margin contour; extraocular muscle size; orbital tissue displacement; and proptosis. Compared with other large series of primary SS patients, similarities were found with age, xerophthalmia, parotidomegaly, and articular involvement. Differences included a lower incidence of autoantibodies, xerostomia, and In comparison with SS, Compared with controls, the lacrimal glands were significantly more significantly (P < 0.0001) and prolapsed (P <0.001). Involved glands had blurred margins (P <0.007), caused displacement of adjacent tissues (P = 0.03), and were associated wit h hyThree patients had monoclonal infiltrates, and 1 patient experienced next extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type, 4 years after presentation Conclusions: The criteria used to diagnose primary SS are controversial, but both diagnostic and quantitative immunohistochemical criteria suggest those these patients, with lacrimal gland enlargement resulting from lymphocytic infiltration, represent a new subtype of primary SS. This is clinically important in view of the increased risk of lymphoma associated with SS, compared with idiopathic nonspecific lacrimal inflammation.