The abilities of human cytotoxic T cell (CTL) clones and natural killer (NK) cell clones to inhibit the replication of herpes simplex virus (HSV) in vitro were shown. The specificities of clones inhibiting HSV replication were the same as those of cytotoxicity in HSV type specificity and HLA restriction, i.e. HSV type 1 (HSV-1) and HSV type 2 (HSV-2) common CTL clones inhibited the replication of both HSV-1 and HSV-2 in autologous cells, but not in allogeneic cells. HSV-1-specific CTL clones inhibited the replication of HSV-1 in autologous cells; however, the replication of HSV-2 was not inhibited. NK cell clones inhibited the replication of HSV-1 and HSV-2 in autologous and allogeneic cells. This is the first demonstration that human virus-specific CTL clones and NK cell clones directly limit virus replication in vitro.