Hepatitis delta virus (HDV) infection is the most severe form of viral hepatitis. HDV is a defective RNA viroid that requires the HBsAg from hepatitis B virus (HBV) for transmission. While the disease is considered immune-mediated, adaptive immune responses against HDV are weak. Thus, the role of other immune responses, including those mediated by mucosal-associated invariant T (MAIT) cells, highly enriched in the human liver, must be considered in HDV pathogenesis. Although MAIT cells primarily recognize bacterial vitamin B2 metabolites, they can also become activated by cytokines generally induced during chronic viral hepatitis, such as IL-1b, IL-7, IL-12, and IL-18. Thus, we hypothesized that MAIT cells would be able to respond during chronic HDV infection. To address this, we performed an extensive analysis of MAIT cells in patients with chronic HDV infection and compared the results to HBV mono-infected patients and healthy controls. The results showed a dramatic decline in peripheral blood MAIT cell frequency in HDV-patients as compared to healthy controls. Anti-viral therapy with IFNa led to no apparent recovery of MAIT cells in the chronic HDV patients. In contrast, a more modest decline in MAIT cells was noted in the HBV mono-infected patients. Loss of MAIT cells was significantly associated with increased fibrosis in the patients. However, reduction in peripheral blood MAIT cell levels in chronic HDV was not due to accumulation of these cells in the liver. Remaining peripheral blood MAIT cells in the chronic HDV patients exhibited partly activated and exhausted phenotypes with increased expression of PD-1, CD57, CD38, and HLA-DR. These altered phenotypes were not seen in HBV mono-infection. Finally, ongoing experiments are assessing the functional capacity of MAIT cells in patients with chronic HDV. The present results suggest that MAIT cells are activated, exhausted, and depleted during chronic HDV-infection.