SS is an autoimmune disease. pSS affects exocrine glands predominantly, whereas sSS occurs with other autoimmune connective tissue disorders. Currently, care for patients with SS is palliative, as no established therapeutics target the disease directly, and its pathogenetic mechanisms remain uncertain. B-cell abnormalities have been identified in SS. CXCL13 directs B-cell chemotaxis and is elevated in several autoimmune diseases. In this study, we tested the hypothesis that CXCL13 is elevated in SS in mice and humans and that neutralization of the chemokine ameliorates disease in a murine model. We assayed CXCL13 in mouse models and human subjects with SS to determine whether CXCL13 is elevated both locally and systemically during SS progression and whether CXCL13 may play a role in and be a biomarker for the disease. Cxcl13 expression in salivary tissue increases with disease progression, and its blockade resulted in a modest reduction in glandular inflammation in an SS model. We demonstrate that in humans CXCL13 is elevated in serum and saliva, and an elevated salivary CXCL13 level distinguishes patients with xerostomia. These data suggest a role for CXCL13 as a valuable biomarker in SS, as 74% of patients with SS displayed elevated CXCL13 in sera, saliva, or both. Thus, CXCL13 may be pathogenically involved in SS and may serve as a new marker and a potential therapeutic target.