Highly purified suspensions of intratumoral T lymphocytes, recovered 11 and 13 days after induction of regressing or progressing Moloney sarcomas, were compared in their ability to lyse specifically the MSC cells used for tumor induction. Cytolytic activity, expressed in terms of lytic units/106 T cells, was similar for intratumoral T cell suspensions obtained 11 days after induction of either regressing (3.1 ± 1.3 LU/106 T cells) or progressing (4.3 ± 1.8) neoplasma. By 13 days post induction, regressing tumors contained T lymphocytes with an increased cytolytic activity (11.1 ± 4.5) whereas those from progressing tumors were strikingly less able to kill MSC cells (≤ 0.2). This loss in cytotoxicity could not be attributed to errors associated with the enzymatic disaggregation method, inhibition by copurified endogenous tumor cells, or immunosuppression induced by viral infection. The changes in functional activity of intratumoral T lymphocytes from the two types of sarcoma appeared to be correlated with the stage of neoplasia. In this model system, cytolytic activity of T lymphocytes increased during spontaneous tumor regression whereas losses in cytotoxicity occurred coincident with the onset of inexorable progression.