Background: Primary Sjogren's syndrome (pSS) is an autoimmune disease that leads to salivary and lacrimal gland dysfunction. The adaptive immune response associated with T helper-2 lymphocytes appears to be altered in these patients. Therefore, the objective of this study was to determine the salivary levels of interleukin (IL)-6, IL-5, and IL-4 in patients with pSS when compared to a healthy control (HC) group. The secondary objectives were to study whether ILs levels in pSS patients were associated with salivary flow, patient-reported outcomes (PROMs) for xerostomia and oral health quality of life (Oral Health Impact Profile-14 [OHIP-14]), pSS classification criteria and presence of extraglandular manifestations. Methods: A case-control study was conducted in 36 patients with pSS and 35 HCs. Cytokine levels were measured using high-sensitivity multiplex map human immunoassays. Unstimulated and stimulated whole saliva were collected and patients filled out questionnaires. The Mann-Whitney U test, chi-squared test, and Spearman correlation test were used. Results: Interleukin-6 was significantly higher in pSS patients than in HCs (P =.0001). IL-6 was significantly higher in pSS patients with a positive salivary gland biopsy (P =.04), whole stimulated saliva hyposalivation (P =.02), and presence of musculoskeletal disorders (P =.03). There was a non-significant positive correlation between IL-6 levels and PROMs for xerostomia (r =.31; P =.06) and OHIP-14 (r =.07; P =.68) in pSS patients. Levels of IL-4 and IL-5 were not detected in both pSS and HCs patients. Conclusions: Salivary IL-6 levels are significantly associated with pSS patients, and therefore, it is hypothesized that this biomarker may be useful in the diagnosis and follow-up of this disease.