Multiple lectins with specificity for cell surface glyco-proteins inhibit cellular and humoral immune responses and induce transplantation tolerance. Because cell surface glycoproteins play a significant role in various immune events involving cell to cell interactions and because the mixed lymphocyte culture (MLC) reaction is a prototype of immune phenomenon involving cell to cell interactions as well as an in vitro analogue of graft-destructive immune events, the effect of modification of the cell surface with oxidizing mitogens was investigated. Treatment of responder or stimulator cells with neuraminidase and galactose oxidase (NAGO) or with sodium periodate (IO-4) resulted in marked suppression of alloantigen-induced proliferation and in vitro generation of primary cytotoxic T cells (CTLs) in human MLCs. A prominent coupling of mitogen-induced proliferation to abrogation of MLC was consistently observed with modification of stimulator or responder cell surface with either NAGO or IO-4. The possibility that destruction of receptor sites and/or stimulatory units was responsible for the suppression of MLCs was excluded by restoring both proliferation and generation of primary CTLs by reduction of mitogen-oxidized cell surfaces with sodium borohydride. The ability of polyclonal activators to inhibit antigen-specific responses might be useful in abrogating unfavorable alloimmune responses.