A 6‐year‐old, intact male English Bulldog presented for evaluation of weakness. Physical examination revealed mildly pale mucous membranes and ophthalmologic alterations. A complete blood cell count was performed on the Urit Smart V5 and the Sysmex XN‐1000V, and showed several hematologic discrepancies between the analyzers. The Urit reported marked leukocytosis and thrombocytosis, and the Sysmex reported marked thrombocytosis on the impedance and optical RET channel but mild thrombocytopenia on the optical PLT‐F channel. On the blood smear examination, there was an abundant proteinaceous material compatible with cryoglobulins. The red blood cell exhibited a notable degree of poikilocytosis. The number of leukocytes was found to be correlated with the Sysmex total white blood cell count, while the platelet count demonstrated a better correlation with the optical PLT‐F channel from the Sysmex. Centrifugation of the blood in a capillary tube (at room temperature) identified a cryoglobulin precipitate. Additionally, the blood was reanalyzed soon after warming it to 37°C, which partially corrected most of the interferences. The serum protein electrophoresis demonstrated a marked hyperproteinemia with mild hypoalbuminemia and a marked hypergammaglobulinemia. On diagnostic imaging, a mild splenomegaly was noted. Cytology of the spleen showed Leishmania infantum infection, plasma cell hyperplasia, and extramedullary hematopoiesis. This is the first description of a dog infected with Leishmania. infantum with concurrent monoclonal hypergammaglobulinemia and cryoglobulinemia. We present a detailed description of the interference of cryoglobulin with the Urit Smart V5 and the Sysmex XN‐1000V, along with the usefulness of Sysmex PLT‐F in this condition.