Objective To study the histopathological changes of relevant intemal organs of Macaca mulatta infected with Plasmodium knowlesi ( P. knowlesi). Methods Histopathological examination of 3 monkeys who died of P. knowlesi infection, 2 P. knowlesi infected monkeys who died of treatment failure with artesunate suppository and 1 P. knowlesi infected monkey that was cured by piperaquine phosphate (PQP) but died of trauma and necrosis of the fore limb. Results The heart, liver, spleen, lung, kidney, brain, pancreas, parathyriod, pituitary and lymph nodes showed severe pathological changes in 3 monkeys (No. 1, 7 and 12) who died of P. knowlesi infection and 1 infected monkey (No. 72) who died of treatment failure with artesunate suppository. Red blood cells containing rmalarial parasites and pigments were concentrated in the capillaries of these organs. Malarial pigments were deposited in many organs or phagocytized by macrophages in 1 monkey (No. 131 ), it was cured by piperaquine phosphate but died of trauma and necrosis of the fore limb; cellular atrophy and disappearance of pancreatic islets, parathyroid and pituitary cells were also observed. One monkey (No. 33) treated with artesunate suppository, showed that blood parasites became negative but recrudesced and pituiary later died from a gavage accident. Its organs showed a significant difference to those of the infected monkeys receiving no treatment. Only the liver Kupffer cells and cerebral matrix contained malarial parasites and pigments; many relevant intemal organs showed repair. Conclusion The pathological changes of relevant internal organs of Macaca mulatta infected with P. knowlesi were examined in detail, especially cellular atrophy and the disappearance of pancreatic islets, parathyoid and pituitary cells and myolysis of cardiac muscles. These changes have not previously been reported elsewhere.