The expression of viral antigens on the surfaces of lymphocytic choriomeningitis virus (LCMV)-infected L-929 cells peaked 2-4 days postinfection and thereafter precipitously declined. Little or no viral antigen was expressed on the plasma membrane surfaces of persistently infected cells, but LCMV antigens were clearly present in the cytoplasms of most of those cells. Cells early after acute infection (days 2-4) were lysed by both virus-specific antibody and complement (C) and immune T lymphocytes. To the contrary, antibody and C did not kill persistently infected cells, but T lymphocytes did kill such cells although at a lower efficiency than acutely infected cells. The expression of viral antigens on the surfaces of infected cells was regulated by the virus- cell interaction in the absence of immune reagents and was closely associated with defective interfering (DI) LCMV interference. DI LCMV, per se, blocked the synthesis and cell surface expression of LCMV antigens, and DI LCMV generation immediately preceded a precipitous reduction in cell surface antigenicity during the acute infection. Persistently infected cells produced DI LCMV but no detectable S LCMV. Peritoneal cells isolated from mice persistently infected with LCMV resembled cultured persistently infected cells in their reduced expression of cell surface antigens and their resistance to LCMV superinfection. It is proposed that DI virus-mediated interference with viral protein synthesis may allow cells to escape immune surveillance during persistent infections.