Sex differences in a NOD.H2h4 murine model of Sjögren's syndrome were analyzed. Compared to males, female NOD.H2h4 mice have increased severity of sialoadenitis and have a significantly increased percentage of CD4+ T cells in salivary gland infiltrates. CD4 + T cells in female infiltrates produce more Th2 and Th17 cytokines than in males, while males have greater Th1 responses. Females also have enhanced B cell responses, with higher levels of SSA and SSB serum antibodies, and B cell activation factor F (BAFF). Thus, sex has a strong impact on the severity of murine Sjögren's syndrome by affecting the immune mechanisms driving the autoimmune inflammation.