Cane toads were introduced into Queensland in 1936 in an attempt to control the sugar cane beetle. Since then, they have dispersed across a million square kilometers, arriving in Darwin, Northern Territory, in 2005. Despite intense interest in the diseases of this invasive amphibian species, no infectious or parasitic diseases that produce significant mortality have been identified in wild cane toads. In August 2014 (“dry” season), toad ecologists noticed numerous dead, or emaciated and weak wild cane toads in the vicinity of their research station near Darwin. Although wild toads are usually thin during the dry season, the degree of emaciation and behavior of the toads was unusual. Euthanasia, necropsy and histopathology of a wide range or organs was performed on several emaciated weak toads and several relatively normal toads from the local population. In addition, several toads were sampled from a neighboring population, 30 km away. All toads from the local population had some degree of colitis, ranging from severe extensive ulcerative pyogranulomatous colitis in emaciated weak toads to less severe, more proliferative, and lymphoplasmacytic colitis in relatively normal toads. In all toads in which there was colonic mucosal epithelium remaining, there were amoebae intermingled with the epithelial cells. Histologically appreciable amoebic colitis was not evident in the toads from the neighboring population. During December (“wet” season), when toads are generally in better body condition, several toads in excellent body condition sampled from the local population did not have histological evidence of amoebic colitis, while relatively thin toads did. Efforts are underway to identify the pathogenic amoebae, and develop a means to diagnose the infection in live toads to enable investigation of the ecology of the host-parasite relationship.