Familial hemophagocytic lymphohistiocytosis 2 (FHL2) is a cytokine storm syndrome characterized by immune hyperactivation with viral infection due to a CD8 T cell cytotoxic killing defect secondary to a perforin deficiency. As most studies of FHL2 mice have used pathogen na?ve animals， the effects of immune memory on FHL2 are understudied. We utilized an immunization model of the perforin-deficient mouse to study the effects of immune memory on FHL2. Prior CD8 T cell specific antigen exposure leads to enhanced HLH disease with increased morbidity and decreased time to mortality. Enhanced disease is associated with altered cytokine production and T cell proliferation. Response to IFNγ blockade is reduced and TNFα gains a pathogenic role， while blockade of the IL-33 receptor ST2 remains effective. These results suggest that pre-existing immune memory may worsen outcome and alter treatment response for FHL2 patients who may not be na?ve to their immune triggers.