Fatal (Panthera tigris) cytauxzoonosis was diagnosed in a 7-year-old female white tiger. The tiger presented with a 2-day history of anorexia and lethargy. She was mildly dehydrated, with a temperature of 105.2 F and a hematocrit of 26%. Over the next day, icterus developed, and her physical condition progressed to recumbency, coma, and death. Hematologic findings obtained shortly before death included icteric plasma, severe thrombocytopenia, mild anemia, hematuria, and parasites consistent with Cytauxzoon felis in circulating erythrocytes. Gross necropsy findings included generalized icterus, generalized petechiae and ecchymoses, splenomegaly, and peribronchial edema. Histologic changes included large numbers of intravascular macrophages containing developmental stages of Cytauxzoon felis that partially or completely occluded blood vessels in the lung, spleen, liver, and bone marrow. Except for an experimental infection of a bobcat, fatal cytauxzoonosis has not previously been diagnosed in felids other than domestic cats. These findings raise questions regarding the pathogenicity of this organism in felids and may impact husbandry and interstate transfer of captive large cats.