Although coxsackie B viruses (CBVs) are known to cause viremia during acute infection, the role of the blood cells as a target for virus replication is poorly understood. We have analyzed the susceptibility of human peripheral blood mononuclear cells (PBMCs), granulocytes, bone marrow (BM) cells, and lymphoid cell lines to coxsackievirus B3 infection. Lymphoid cell lines with B- and T-cell characteristics (Raji and Molt-4, respectively) supported virus replication to high titers and virus protein synthesis was detected by metabolic labeling and immunoprecipitation. CBV3 synthesis in the U937 cell line with mononuclear phagocytic characteristics was very limited. The virus was able to infect a small proportion of leukocytes and BM cells, and intracellular virus antigens were detected by immunofluorescent staining. However, only a diminutive amount of infectious virus was produced in isolated PBMCs and granulocytes, and no virus protein synthesis was detected by metabolic labeling and immunoprecipitation in these cells.