When 14C-labeled cyclophosphamide and nitrogen mustard were incubated separately with normal lymphocytes and lymphocytes from patients with chronic lymphocytic leukemia, the amount of radioactivity associated with the normal cells far exceeded that detected on the leukemic lymphocytes. This comparative diminution may be analogous to the impaired PHA response and excess surface immunoglobulin which serve as identifying markers of the malignant B cell. Cytotoxicity and neuraminidase experiments indicated that drug uptake by lymphocytes is not capricious and may occur in an optimum, predetermined fashion. Although surface uptake and therapeutic response are not necessarily directly interrelated, initial peripheral contact with an antineoplastic agent may be an essential step which modifies tumor sensitivity or resistance. Cancer 36:1959–1965, 1975