Histopathologic and immunohistologic studies were performed in two cases of fatal cerebral malaria. On admission, both patients were in unarousable coma with hyperparasitemia. Examination of the tissue sections from various organs showed parasite sequestration in both cases with more extensive area of sequestration in case 1 than in case 2. A panel of monoclonal antibodies against cytokines applied to these tissues clearly detected tumor necrosis factor-alpha (TNFα), interferon-gamma (IFNγ), interleukin-1B (IL-1β), and IL-10 in the tissues from brain and liver of case 1. A different cytokine profile, IL-4 and IL-10, was found in the brain tissues of case 2; no TNFα nor IFNγ was detected. There was no cytokine detected in the tissues of other organs in either case. Results of the study suggest that histopathology in the brain of fatal cerebral malaria may be associated with focal accumulation of cytokines. Additionally, the type of cytokines produced locally in a particular tissue during malaria infection may be regulated by the degree of regional parasite sequestration.