The spleen is critical for host defense against pathogens, including Plasmodium falciparum. It has a dual role, not only removing aged or antigenically altered erythrocytes from the blood but also as the major lymphoid organ for blood-borne or systemic infections. The human malaria parasite P. falciparum replicates within erythrocytes during asexual blood stages and causes repeated infections that can be associated with severe disease. In spite of the crucial role of the spleen in the innate and acquired immune response to malaria, there is little information on the pathology of the spleen in human malaria. We performed a histological and quantitative immunohistochemical study of spleen sections from Vietnamese adults dying from severe falciparum malaria and compared the findings with the findings for spleen sections from control patients and patients dying from systemic bacterial sepsis. Here we report that the white pulp in the spleens of patients dying from malaria showed a marked architectural disorganization. We observed a marked dissolution of the marginal zones with relative loss of B cells. Furthermore, we found strong HLA-DR expression on sinusoidal lining cells but downregulation on cordal macrophages. P. falciparum infection results in alterations in splenic leukocytes, many of which are not seen in sepsis.