Twenty pigs were inoculated with a virulent classical swine fever virus isolate to determine the mechanism responsible for thrombocytopenia using histopathologic, ultrastructural, and immunohistochemical (detection of viral antigens gp55 and FVIII-rag) techniques. In animals euthanatized at 2, 4, and 6 days postinoculation (dpi), clusters of granular material staining positive for FVIII-rag were observed in splenic cords, the marginal zone, hepatic sinusoids, and the perisinusoidal space. Moreover, numerous macrophages in these areas were swollen and displayed an intensely positive granular and cytoplasmic reaction. Cell alterations indicative of platelet activation and secretory and phagocytic activation of resident macrophages were also observed in these sites at 2 and 4 dpi. These results suggest that the thrombocytopenia observed in pigs is caused in the first instance by massive activation and subsequent phagocytosis of platelets secondary to the release of platelet-activating factors by activated macrophages.