Systemic viral infection is a known precipitant of vasocclusive crisis in sickle patients, but the mechanism underlying this clinical observation is unknown. In the present studies, human umbilical vein endothelial cells were infected with Herpes simplex virus type 1 (HSV) to model systemic viral disease. The already abnormal adherence of sickle erythrocytes to control endothelium is enhanced 1.8 ± 0.4-fold to HSV-infected endothelium (P < 0.001). This component of potentiated adherence is eliminated by maneuvers that block Fc receptors, it is prevented by tunicamycin, and it is not seen using a mutant HSV that is unable to express the Fc receptor glycoprotein. Thus, the incremental adherence seen here occurs due to expression of Fc receptor activity on HSV-infected endothelium and the consequent recognition of abnormal amounts of IgG on sickle erythrocytes. We conclude that systemic viral infection potentially can induce a novel mechanism for enhancement of erythrocyte adherence to endothelium and that this may increase the likelihood of vasocclusion during viral infection.