After treatment with papain (6 mg/ml) for 1 h, P815 tumor cells became resistant to complement-mediated lysis by mouse alloantibodies of different specificities. Immunofluorescence and absorption studies indicated that this resistance was associated with removel of the corresponding antigenic determinants from the cell surface. In contrast, papain-treated tumor cells were fully susceptible to lysis by rabbit antiserum against P815 cells, indicating a) no alteration of the membrane sensitivity to complement damage, and b) a dissociation between structure and/or localization of allo- and xenoantigens. Papain-treated cells were also completely resistant to lysis by cytolytic T lymphocytes (CTL) during the first 60 min after completion of the enzyme treatment. Susceptibility to lysis by either CTL or alloantibody and complement reappeared within a few hours after incubation in culture medium and was virtually normal by 6 h. Treatment of P815 cells with trypsin (2 mg/ml) had no effect on either humoral or cellular lytic activities.