In response to nematode infection, the host presumably attempts to create an unfavorable environment to prevent larval penetration of the host and to expedite parasite expulsion from the gut. In this study, we have used W/WV mice with or without mast cells after bone marrow reconstitution (BMR-W/WV) to examine the role of mast cells in the host response. W/WV, BMR-W/WV, and wild-type (+/+) mice were infected with Trichinella spiralis. Infected W/WV mice exhibited less tissue damage and experienced a delay in worm expulsion and a greater degree of larval penetration of the gut leading to encystment in skeletal muscle. Tissue injury was greater and worm expulsion was normalized in BMR-W/WV mice, but larval penetration remained unchanged. Spontaneous contractile activity of jejunal muscle was disrupted in W/WV mice, as was the contractile response to carbachol. These abnormalities were also present in BMR-W/WV mice. These results indicate that mast cells mediate tissue damage and contribute to the timely expulsion of nematodes from the gut during primary infection.