Tapeworms alter the physiological environment of the host's small intestinal lumen by contracting the intestinal smooth muscle, thereby slowing the transit of intestinal contents. We hypothesize that parasite-to-host molecular signaling is responsible for the specific patterns of small intestinal smooth muscle contraction observed both during tapeworm infection and after the infusion of tapeworm-secreted molecules into the intestinal lumen of unanesthetized rats. Of the tapeworm-secreted compounds tested, only lumenal infusion of guanosine 3′,5′-cyclic monophosphate (cGMP) induced contractile patterns that mimic those observed during tapeworm infection. The response to cGMP occurred in a concentration-dependent fashion. Our study clearly demonstrates that cGMP can serve as an extracellular signal molecule regulating small intestinal motility mechanisms in vivo.