AbstractA 9‐year‐old neutered male cat, previously test‐positive for feline immunodeficiency virus (FIV), was presented with an history of vomiting, hyporexia, and weight loss. Panleukopenia was identified on complete blood counts, and bone marrow evaluation revealed ineffective granulocytic hyperplasia and rare neutro‐, erythro‐, and rubriphagocytosis. Prednisolone was initiated with no response, and progression to pancytopenia occurred. On abdominal ultrasonographic examination, splenomegaly was present. PCR testing was positive for Candidatus Mycoplasma haemominutum and IgG antibodies against Toxoplasma gondii were detected (titer 1:2560). Treatment with antibiotics, feline recombinant interferon‐ω, chlorambucil, mycophenolate, and raltegravir was implemented with no clinical improvement, and splenectomy was performed. Cytologic evaluation of splenic aspirates revealed exuberant neutro‐, erythro‐, and rubriphagocytosis. Histopathology of the spleen also showed many erythrophagocytic macrophages with no evidence of malignancy, and a diagnosis of hemophagocytic syndrome (HS) was made. The WBC count and hematocrit reached reference values 1 day and 3 months, respectively, after splenectomy. The cat was treated with cyclosporine and lomustine. Disease progression led to the development of septic hepatitis, and the cat was euthanized. To our knowledge, this is the first case of presumptive HS in cats that might have been associated with FIV, Toxoplasma gondii, and Candidatus Mycoplasma haemominutum co‐infection.