Abstract Human peripheral blood lymphocytes (PBL) were incubated (sensitized) for 6 days on autologous or allogeneic fibroblast monolayers either uninfected or infected with measles virus. The sensitized PBL were then tested, in a 6-hr 51Cr-release assay, against autologous and allogeneic measles virus-infected and uninfected fibroblast target cells. When the PBL had been sensitized on autologous infected monolayers, they were cytotoxic to both autologous and allogeneic measles-infected targets but not to uninfected targets or to targets infected with paramyxovirus I (Sendai virus). Likewise, PBL sensitized on uninfected autologous (or allogeneic) monolayers had no cytotoxic activity against any of the infected or uninfected target cells. When the PBL had been sensitized on allogeneic infected monolayers, they were cytotoxic to measles-infected targets that were autologous either to the PBL themselves or to the sensitizing monolayer. These sensitized PBL were not, however, cytotoxic against third-party infected targets that were totally allogeneic to both the PBL and the sensitizing monolayer. Subpopulation depletion studies revealed at least two different effector lymphocytes in the sensitized PBL. One such effector was a T cell whose activity would be generated on autologous measles-infected monolayers but not on allogeneic infected monolayers. The cytotoxic activity of this cell was measles virus specific, and it required that the effector recognize as self antigens of the MHC on the target cell. The second effector cell also required in vitro generation but could be so generated on both allogeneic and autologous measles-infected, but not uninfected, monolayers. It was a non-T cell that had a receptor for the Fc fragment of IgG but lacked nonspecific esterase activity. This effector was measles virus specific, in that it failed to lyse either uninfected targets or targets infected with Sendai virus (the latter of which could be lysed by fresh PBL). When this non-T effector was generated on allogeneic infected monolayers, its cytotoxic activity showed an unusual form of MHC-related specificity, in that it lysed infected target cells autologous to either the PBL or the sensitizing monolayer but not infected third-party target cells allogeneic to both. Evidence was discussed which argued that our non-T effector was neither a conventional K nor NK cell.