Nine of 16 dogs inoculated with 200 infective heartworm larvae developed caval syndrome (CS) of heartworm disease (HWD). There was no difference between dogs that did and did not develop CS with regard to total heartworm burden, burden relative to body weight, or female heartworm burden, indicating that factors other than worm mass are involved in the pathogenesis of CS. Male dogs were twice as frequently affected as females, although this finding was not statistically significant. Dogs afflicted with CS exhibited radiographic, pathologic, and hemodynamic evidence of chronic HWD. In a model of single heartworm exposure, these findings strongly support the theory that CS develops due to retrograde migration of adult worms from the pulmonary arteries and right ventricle to the right atrium and venae cavae. Pulmonary artery pressures were dramatically and significantly greater in dogs with CS (60 +/- 18 torr) as compared to non-CS (30 +/- 4 torr) dogs with equal worm burdens.