The formation of ectopic germinal centers (GC) has been described in Sjögren's syndrome (SS), although little is known about the molecular basis of this phenomenon. These structures are a focus of in situ autoantibody production and have been hypothesized to be involved in lymphomagenesis in SS patients. Serum cytokines also play an important role in SS pathogenesis in part via immune dysregulation and may therefore contribute to ectopic GC formation. Herein, highly multiplex cytokine screening of SS patients with (SSGC+) and without (SSGC-) GC formation was done to identify cytokine profiles that correlate with this phenomenon. Serum levels of B-cell activating factor (BAFF) were also screened as a potential biomarker of immune dysregulation in SS and SSGC formation. Univariate analysis demonstrated that serum levels of a broad spectrum of immune and inflammatory modulating cytokines are upregulated in SSGC+ and SSGC- patients relative to unaffected controls IL-1beta, IL-2, IL-6, IL-15, IFN-gamma and CCL4 (MIP-1beta). SSGC+ patients were distinguished from healthy individuals by higher levels of IL-4, IL-10, GM-CSF, IFN-alpha, CCL3 (MIP-1alpha), CCL11 (Eotaxin) and BAFF, while SSGC+ and SSGC- patients differed in CCL2 (MCP-1) expression. Discriminant function analysis (DFA), a multivariate discrimination method that uses observed differences to characterize groups when casual relationships are not well understood, was employed to identify a subset of these biomarkers that maximally discriminate among SSGC+, SSGC- and unaffected individuals. The biomarker having the strongest discriminatory power identified by DFA besides CCL11 (Eotaxin) and IFN-gamma was BAFF. The variables identified by DFA are interdependent and are often of mechanistic significance to the pathologic states they distinguish, suggesting that these factors modulate SS pathology and SSGC formation in a synergistic manner.