Cross-reactivity of TNP[trinitrophenol]-immune, virus-immune and alloreactive murine cytotoxic thymus-derived (Tc) cells was investigated at the level of target cell lysis. Alloreactive Tc cells cross-reacted on TNP-modified and unmodified 3rd party targets and on syngeneic TNP-modified targets but did not cross-react on syngeneic virus-infected targets. TNP-immune Tc cells showed marked cross-reactivity on certain allogeneic targets modified by TNP (loss of H-2 restriction) and on certain unmodified allogeneic targets but did not cross-lyse virus-infected syngeneic targets. Targets treated with TNP-Sendai virus were not lysed by TNP-immune Tc cells, but Tc cells stimulated by cells treated with TNP-Sendai virus lysed such targets readily. Tc-cell recognition of foreign H2 antigens and TNP-modified self-H-2 antigens are probably mechanistically similar (possibly via one receptor), whereas recognition of viral plus H-2 antigens is different (possibly via two receptors). Virus-immune Tc cells ubiquitously exhibited strong cross-reactivity on syngeneic TNP-modified targets using pox-, arena-, alpha-, myxo- and paramyxoviruses for Tc-cell induction. The lysis of virus-infected targets by virus-immune Tc cells could be inhibited by cold TNP-modified competitors. Some individual virus-immune Tc cells could recognize both types of target cells. This genuine cross-reactivity at the effector level was not observed at the level of induction of secondary responses, since the cross-reactive subset of virus-immune memory Tc cells could not be activated by TNP-modified stimulator cells but could be activated by virus-infected stimulators. Requirements for stimulation of precursor Tc cells may sometimes be different from antigenic requirements for recognition and lysis of effector Tc cells.