A histopathological study was performed to clarify the characteristics of granuloma formation and liver fibrosis in Schistosoma mekongi infection in comparison with S. japonicum infection. Mice were exposed to S. mekongi (Laotian strain) and S. japonicum (Japanese strain) cercariae, and were dissected at 6, 8, 12, 16, and 20 weeks post-exposure. In the liver, granulomas in S. mekongi infection were cellular, initially organized with foam cells, and continuously appeared in the intralobular area, while granulomas in S. japonicum infection were fibrous and did not continuously appear in the intralobular area. Portal fibrosis was not seen in S. mekongi infection, but was commonly seen in S. japonicum infection in the later weeks. Granulomas in the small intestine were seen mainly in the submucosa with foam cells in S. mekongi infection and without foam cells in S. japonicum infection. The lung granulomas contained mainly histiocytes in both S. mekongi and S. japonicum infection. The absence of portal fibrosis in S. mekongi infection allows schistosome eggs to infiltrate into the intralobular area continuously, which can be what lies behind the ultrasonographic differences; the echogenic network pattern as was seen in S. japonicum infection, has not been noted in S. mekongi infection.