Exotic animal and plant species introduced into the Australian continent often imparted catastrophic effects on the indigenous fauna and flora. Proponents of biological control introduced the South American Cane Toad (Bufo marinus) into the sugar cane fields of Queensland in 1935. The Cane Toad is one of the most toxic bufonids, and when seized by naïve Australian predators, the toxin usually kills the attacker. One group of Australian squamate reptiles that are very susceptible to Cane Toad toxins is varanid lizards. Prior to Cane Toad invasion of our study area, the Adelaide River floodplain of the Northern Territory of Australia, annual mortality of adult male radio-tagged Yellowspotted Goannas (Varanus panoptes) was very low (two deaths recorded among 20 lizards over three years). After the arrival of the toads in October 2005, all radio-tracked goannas were found dead in August 2006 (nine out of nine lizards), most likely after attempting to feed on toads. Our results suggest that invasive Cane Toads place naïve adult male Yellow-spotted Goannas at risk of possibly > 90% mortality. This increase in mortality could reduce the genetic diversity and hamper long-term survival of these large carnivorous lizards.