Soft corals of the family Xeniidae are particularly abundant in Red Sea coral reefs. Their success may be partly due to a strong defense mechanism against fish predation. To test this, we conducted field and aquarium experiments in which we assessed the anti-feeding effect of secondary metabolites of 2 common xeniid species, Ovabunda crenata and Heteroxenia ghardaqensis. In the field experiment, the metabolites of both investigated species reduced feeding on experimental food pellets in the natural population of Red Sea reef fishes by 86 and 92% for O. crenata and H. ghardaqensis, respectively. In the aquarium experiment, natural concentration of soft coral crude extract reduced feeding on experimental food pellets in the moon wrasse Thalassoma lunare (a common reef fish) by 83 and 85% for O. crenata and H. ghardaqensis, respectively. Moon wrasse feeding was even reduced at extract concentrations as low as 12.5% of the natural crude extract concentration in living soft coral tissues. To assess the potential of a structural antifeeding defense, sclerites of O. crenata (H. ghardaqensis lacks sclerites) were extracted and mixed into food pellets at natural, doubled and reduced concentration without and in combination with crude extract at 25% of natural concentration, and tested in an aquarium experiment. The sclerites did not show any effect on the feeding behavior of the moon wrasse, indicating that sclerites provide structural support rather than anti-feeding defense. We conclude that the conspicuous abundance of xeniid soft coral species in the Red Sea is likely a consequence of a strong chemical defense, rather than physical defenses, against potential predators.