The variant best known as the large-colony type of M. mycoides subsp. mycoides is responsible for severe outbreaks of septicemia with coagulopathy in goats. Our objective was to study aspects of the pathogenesis that might explain the coagulopathy, the persistence of mycoplasmas in the blood of septicemic goats, and the host specificity. The endothelial cells of caprine aorta tissue cultured in vitro and exposed to the M. mycoides underwent severe ultrastructural damage. There was no evidence of cytotoxicity to 51Cr-labeled adherent cells from peripheral blood of goats. Complement from goat, sheep, calf and guinea pig was activated by the mycoplasma, resulting in consumption of complement and lysis of mycoplasmas. Goat complement had the poorest mycoplasmacidal effect, whereas guinea pig complement had the highest cidal activity. Complement was activated through the classical pathway, since selective chelation of Ca++ inhibited activation, and serum from C4-deficient guinea pigs was not mycoplasmacidal. Complement activity was restored in chelated serum of sheep, calf and guinea pig after Ca++ supplementation, but not in goat serum, suggesting a difference in the classical pathway activity between these species. Activation of complement may be an important generator of inflammation in this disease. However, species variation in mycoplasmacidal efficiency of complement cannot wholly explain why goats and sheep are susceptible to septicemia and calves and guinea pigs are not. Both endothelial damage and complement activation may be important features of the pathogenesis of tissue damage, and may help explain the coagulopathy in this disease.