Histopathological changes were studied in Swiss albino mice (N:36)which were challenged with the South Indian local strain of Trypanosoma evansi. Each animal was infected with 5×105 trypanosomes intraperitoneally. The animals were examined daily for development of clinical signs and infection status by wet blood-films made from the tail veins. The infected mice were dull and depressed from two days post-infection (DPI) onwards. Systematic post-mortem examination of the infected mice was performed and pathological changes were recorded. The different tissue samples were collected in 10% formalin and were used to study the histopathological changes. Postmortem examination from 3-4 DPI (the maximum period of observation) revealed splenomegaly, hepatomegaly, marked congestion of lungs, presence of fl uid in peritoneal cavity. Histopathologically, heart muscles showed hyaline degenerative changes and haemorrhages. Liver parenchyma revealed congestion of central vein and sinusoids, binucleated hepatocytes and fatty change of hepatic cells. Thickening of interstitial space with mononuclear infiltration, areas of collapse, areas of emphysema, edema and dilated and congested blood vessels were the histopathological changes noticed in the lungs of the infected mice. In the spleen, giant cells aggregation, hyperplasia, thickening of capsule and trabecule were the changes indicating irreversible degeneration. The affected kidney showed inter-tubular hemorrhages in the cortex, medullary hemorrhages, congested glomerulus, atrophied glomerulus, desquamated tubular epithelium and disruption of renal tubules at some places.