Large-bodied mammals living in fragmented habitats are at higher risk of extinction, and such risk can be influenced by ecological factors such as predator-prey system dynamics. These dynamics can be particularly complex for conservation management when one endangered species preys on another endangered species in an isolated or poor-quality habitat. Here we describe predation events observed over 19 months that involved two threatened species: the largest carnivore in Madagascar, the fosa (Cryptoprocta ferox), and three groups of diademed sifaka (Propithecus diadema) in the Betampona Strict Nature Reserve. This site is a 22 km2 low-altitude rainforest that is surrounded by agricultural land and isolated from larger forest corridors. We aim to (1) assess the behavioral changes of P. diadema in response to fosa attacks and identify any antipredator strategies that they adopted, and (2) quantify the frequency of fosa attacks and the predation impact on the sifaka population. We report five direct observations of fosa predation attempts (one successful), the discovery of a dead sifaka with evidence of fosa predation, and the disappearance of three individuals. We describe the observed attacks and compare the sifaka activity budgets and movement patterns before and after the events. To escape the predator, sifakas fled short distances, hid, and remained vigilant. The impact of predation, combined with low reproductive rates and potentially high inbreeding of this isolated diademed sifaka population, could affect the survival of this species in Betampona.Given the compounding effects of habitat isolation and high hunting pressure, community-specific conservation strategies should incorporate predator-prey dynamics via longitudinal monitoring of predator and prey population densities and quantifying the predation pressure between them.