We investigated the hypothesis that the squirting of blood from orbital sinuses by Texas horned lizards (Phrynosoma cornutum) is an antipredator defense against some mammalian species. Coyotes (Canis latrans) were tested for the first time. As expected, Texas horned lizards squirted blood in response to coyote attacks, and coyotes exhibited startle response, avoidance response, or both as a result of these events. Whereas lizard carcasses mixed into normal food-mash elicited regurgitation by coyotes, possibly due to physical effects, blood of horned lizards similarly mixed into food did not. Coyote responses to simulated squirts of 5 compounds, including blood of horned lizards, into 3 potential sensory target areas (eyes, nose, and mouth) strongly suggested that aversive effects were mediated by receptors in the oral or nasal cavities. Coyote responses were more frequent to delivery of blood plasma and whole blood of Phrynosoma to buccal and nasal membranes than to delivery of plasma and blood from spiny lizards (Sceloporus jarrovii) or to delivery of a saline control to these membranes. We concluded that Texas horned lizards squirt blood from sinuses surrounding the eyes during attacks by canids, such as coyotes, and that this blood affects oral receptors, causing a negative response in coyote attack behavior that potentially increases survival of the lizards.