Hemophagocytic lymphohistiocytosis (HLH) comprises an expanding group of disorders associated with overactive immune cells that mediate significant tissue damage. Prior studies reveal that persistence of activated antigen presenting cells drives hyperinflammation in HLH. The immunoproteasome is known to play a role in antigen presentation on class I major histocompatibility complex (MHC) and immune effector cell function. Accordingly, we hypothesized that immunoproteasome inhibition might decrease the cellular and molecular hyperinflammatory response in HLH. Supporting this notion, we find that immunoproteasome inhibition significantly reduces in vitro antigen-specific CD8 T cell proliferation and interferon-gamma (IFNg) production. To examine the effects of immunoproteasome inhibition in an in vivo model of primary (genetic) HLH, lymphocytic choriomeningitis virus (LCMV)-infected perforin-deficient (Prf1-/-) mice were treated with the selective immunoproteasome inhibitor zetomipzomib on varying days post-infection. On days 8-10, immune cell subsets, cytokine production, and lymphocytic tissue infiltration were assessed. Untreated LCMV-infected animals developed marked organomegaly with increased effector T cells, neutrophils, and elevated levels of serum IFNg. Each of these parameters was significantly diminished in zetomipzomib-treated animals. Upon ex vivo antigen stimulation, CD8 T cells from zetomipzomib-treated mice exhibited significantly decreased IFNg production. Together, these data highlight the role of persistent antigen presentation in disease development and suggest that immunoproteasome inhibition shows promise as a potential therapeutic strategy for HLH. Further studies are ongoing to optimize the effects and decipher underlying mechanisms. Hemophagocytic lymphohistiocytosis (HLH) comprises an expanding group of disorders associated with overactive immune cells that mediate significant tissue damage. Prior studies reveal that persistence of activated antigen presenting cells drives hyperinflammation in HLH. The immunoproteasome is known to play a role in antigen presentation on class I major histocompatibility complex (MHC) and immune effector cell function. Accordingly, we hypothesized that immunoproteasome inhibition might decrease the cellular and molecular hyperinflammatory response in HLH. Supporting this notion, we find that immunoproteasome inhibition significantly reduces in vitro antigen-specific CD8 T cell proliferation and interferon-gamma (IFNg) production. To examine the effects of immunoproteasome inhibition in an in vivo model of primary (genetic) HLH, lymphocytic choriomeningitis virus (LCMV)-infected perforin-deficient (Prf1-/-) mice were treated with the selective immunoproteasome inhibitor zetomipzomib on varying days post-infection. On days 8-10, immune cell subsets, cytokine production, and lymphocytic tissue infiltration were assessed. Untreated LCMV-infected animals developed marked organomegaly with increased effector T cells, neutrophils, and elevated levels of serum IFNg. Each of these parameters was significantly diminished in zetomipzomib-treated animals. Upon ex vivo antigen stimulation, CD8 T cells from zetomipzomib-treated mice exhibited significantly decreased IFNg production. Together, these data highlight the role of persistent antigen presentation in disease development and suggest that immunoproteasome inhibition shows promise as a potential therapeutic strategy for HLH. Further studies are ongoing to optimize the effects and decipher underlying mechanisms.