©2016 Wolters Kluwer Health, Inc. Purpose: The purpose of this study is to explore the role of the adaptive immune system in patients with aqueous-deficient dry eye (ADDE) and lipid-deficient dry eye (LDDE). Methods: Patients (n = 29) with moderate to severe dry eye (dry eye workshop [DEWS] severity grading scheme) were enrolled in a crosssectional study and classified as ADDE (Schirmer ≤ 10), LDDE (abnormal meibum), combined (meeting both criteria), or generic (meeting neither criterion). Tears were collected by Schirmer strips, and samples for both eyes were pooled for each subject. Thirty micrograms of total protein was used in a normalized volume for microarray analysis (Quantibody Human Inflammation Array 3; RayBiotech). Six markers of TH1 cells (interferon [IFN]g, interleukin [IL]-2), TH2 cells (IL-4, IL-5, IL-13), and TH17 cells (IL-17) were assessed. Results: ADDE demonstrated the highest total cytokine concentration, followed by the LDDE, combined, and generic groups. IFNg and IL-2 were detectable in all subgroups. IL-4, -5, and -13 were detectable in ADDE and LDDE, but only IL-13 was detected in both the combined and generic groups. IL-17 was present in the ADDE, LDDE, and combined groups. Conclusions: TH1 cells seem to be involved in all forms of dry eye. ADDE and LDDE seem to be mediated by TH1, TH2, and TH17 cells. The combined-mechanism group is mediated by TH1 and TH17 cells, and generic dry eye seems to be mediated by TH1 cells only. ADDE has the greatest overall T-cell-mediated pathophysiology compared with the other subgroups, which is consistent with previous reports of improved efficacy with antiinflammatory therapy in these patients.