Primary Sjögren's syndrome (SS) is characterized by chronic periductal inflammatory infiltrates in the salivary glands. Several previous studies have indicated that the ductal epithelia of SS patients play a pro-inflammatory role and manifest an intrinsically activated status, as demonstrated in cultured non-neoplastic ductal salivary gland epithelial cell (SGEC) lines. Herein, we investigated the activation of inflammasomes in the salivary epithelia of SS patients and non-SS controls, using salivary biopsy tissues and SGEC lines. The ductal epithelial cells of SS patients were found to display significant activation of the AIM2 (absent in melanoma-2) inflammasome. Such activation occurred in a cell-autonomous manner, as it was illustrated by the constitutively high expression of AIM2 activation-related genes, the presence of cytoplasmic ASC specks and the increased spontaneous IL-1β production observed in patients' SGEC lines. Since AIM2 activation is known to occur in response to cytoplasmic DNA, we further searched for the presence of undegraded extranuclear DNA in the SGEC lines and SG tissues of patients and controls. This investigation revealed marked cytoplasmic accumulations of damaged genomic DNA that co-localized with AIM2 in the specimens of SS patients (but not controls). The SGEC lines and the ductal tissues of SS patients were also found to manifest impaired DNase1 expression and activity, which possibly denotes defective cytoplasmic DNA degradation in patients' cells and AIM2 triggering thereof. In corroboration, DNase1-silencing in normal SGEC was shown to lead to high AIM2-related gene expression and IL-1β production. Our findings indicate that the cell-intrinsic activation status of ductal epithelia in SS patients owes to persistent epithelial AIM2 activation by aberrant cytoplasmic DNA build-up.