Although compelling genetic and serologic evidence implicate target cell (TC) MHC antigens in specific cytotoxic T lymphocyte (CTL)-TC interaction leading to lysis, it is not entirely clear whether TC recognition through an MHC determinant(s) is a prerequisite for lysis to occur. In fact the finding that both specific and nonspecific TC are lysed equally well in lectin-dependent cell-mediated cytotoxicity (LDCC) challenges the necessity for TC MHC involvement in the cytolytic process beyond providing the basis for specificity in direct (nonlectin-dependent) CTL-mediated lysis. In the present paper we present evidence suggesting that even in nonspecific LDCC, as well as in nonspecific lymphocyte-mediated lysis of TC oxidized by periodate treatment or by galactose oxidase (ODCC), TC MHC components are required for lytic interactions with cytotoxic effector cells. This conclusion is based on 3 types of experimental evidence: 1) cells displaying reduced amounts of MHC proteins are poor targets in LDCC; 2) removal of H-2 by papain renders murine target cells refractory to lysis in LDCC, even though Con A binding is only slightly reduced; 3) antisera to target cell H-2-coded products block lysis in both LDCC and ODCC, whereas antisera to other cell surface antigens do not. A theory explaining nonspecific effector target interaction leading to lysis based on involvement of CTL receptor(s) and TC MHC components is presented.