Chronic infections with the human malaria parasite Plasmodium falciparum depend on antigenic variation. P. falciparum erythrocyte membrane protein 1 (PfEMP1), the major erythrocyte surface antigen mediating parasite sequestration in the microvasculature, is encoded in parasites by a highly diverse family of var genes. Antigenic switching is mediated by clonal variation in var expression, and recent in vitro studies have demonstrated a role for epigenetic processes in var regulation. Expression of particular PfEMP1 variants may result in parasite enrichment in different tissues, a factor in the development of severe disease. Here, we study in vivo human infections and provide evidence that infection-induced stress responses in the host can modify PfEMP1 expression via the perturbation of epigenetic mechanisms. Our work suggests that severe disease may not be the direct result of an adaptive virulence strategy to maximize parasite survival but that it may indicate a loss of control of the carefully regulated process of antigenic switching that maintains chronic infections.