Cytotoxic T lymphocyte effector cells specific for a defined class I antigen can kill target cells displaying a wide range of different class I proteins in the presence of certain lectins and oxidizing agents. However, optimal lysis of the target cell (TC) still requires interaction of the CTL with the TC class I proteins. This raises the question of how the lectin or oxidizing agent alters the system in such a way that an "inappropriate" CTL-TC interaction takes place, in a class I-dependent manner. In this study we show that if papain-sensitive molecules are cleared from the TC surface and are allowed to regenerate in the presence of tunicamycin, the cells still serve as targets in direct, class I antigen-specific CTL killing, but not in LDCC or ODCC. Target cells treated in this way display N-linked carbohydrate-less class I proteins, and presumably other N-linked carbohydrate-less, papain-sensitive molecules as well. We present data showing that both types of molecules are important in nonspecific lytic reactions.