Liver fibrosis is a dynamic condition caused by wound-healing in which scar tissue replaces the liver parenchyma following repetitive injuries. It is hypothesized that α-mangostin (AM), the major constituent of the xanthone fraction in extracts of Garcinia mangostana L., may protect the hepatic microvascular bed from thioacetamide (TAA)-induced fibrosis. In the present study, rats were divided into 4 groups: Control rats received no treatment; TAA-treated rats received 150 mg/kg TAA 3 times per week intraperitoneally; AM-treated rats received 75 mg/kg AM twice per week intraperitoneally; and TAA+AM-treated rats received both TAA and AM as described above. Rat livers were processed either for light microscopy or for vascular corrosion casting after 30 and 60 days of treatment. Vascular parameters were measured by 3D morphometry analysis of scanning electron micrographs. AM attenuated hepatocellular injuries and delayed both periportal and pericentral fibrosis in the TAA-treated rats. The comparison of findings at day 30 and 60 showed that TAA-induced fibrotic changes were progressive in time, and that the beneficial effects of AM only became apparent after prolonged treatment. The livers of rats treated with both TAA and AM had less space surrounding the portal vessels, improved preservation of the hepatic microvascular pattern, and minimally altered sinusoidal patterns with few signs of terminal portal venule remodeling. AM therefore partially protected the liver against hepatotoxin-induced fibrosis and the associated microvascular changes. The mechanism of the protective effect of AM on the liver remains to be investigated.