Abstract. Antimalarial drugs are widely used in malaria endemic areas, both for chemoprophylaxis and also empirically to treat patients presenting with fever. Previously, we have reported that chloroquine enhances the severity of Semliki forest virus (SFV) and encephalomyocarditis virus infection. The studies presented herein show that a broad spectrum of antimalarial drugs augmented the replication of SFV in mice, concomitant with greater tissue damage and up-regulation of mRNA levels of various inflammatory cytokine genes, including interleukin-1 receptor antagonist (IL-1Ra), IL-1␣, IL-1, IL-6, IL-12p40, and interferon-␥ inducing factor. Furthermore, chloroquine enhances IL-1Ra production in RAW cells in vitro. Since IL-1Ra is known to be up-regulated in a number of viral infections, we propose that a further enhancement of its expression by antimalarials may be responsible for the increased severity of viral infection in our studies. Thus, the widespread use of antimalarials in malaria-endemic areas may predispose the population to viral infections. Further studies are in progress to delineate mechanism(s) involved in cytokine up-regulation and acceleration of viral replication.Cytokines are important mediators in inflammatory pathology of the central nervous system (CNS), including encephalitides and demyelinating diseases such as multiple sclerosis.1 Interleukin-1 (IL-1) is an important cytokine implicated in the host response to injury and infection. 2 The production, secretion, and biologic response of IL-1 is tightly regulated, and a naturally occurring inhibitor, IL-1 receptor antagonist (IL-1Ra), has been demonstrated to prevent binding of IL-1 to its receptor, thereby impairing its further biologic effects. 3 Although IL-1Ra is a competitive inhibitor of IL-1, binding to the receptors with high affinity, high quantities (10-100 times more IL-1Ra than IL-1) are required to abrogate the effects of IL-1. The balance between IL-1 and IL-1Ra probably influences the regulation of the host response, and onset and severity of the inflammatory reaction. In this regard, selective over-production of IL-1Ra could be detrimental to the host when mounting an immune response. Increased levels of IL-1Ra have been noted in a variety of viral infections. [4][5][6][7][8][9] However, the role of IL-1Ra in viral-host interactions has not been clearly elucidated.We have previously shown that chloroquine enhances the severity of symptoms and mortality following Semliki forest virus (SFV) and encephalomyocarditis virus (EMCV) infection, along with an increase in viral titers in various organs.