The prevalence of complement dependent, cold‐reactive lymphocytotoxic serum factors (LT) was studied in 80 untreated patients with Hodgkin'S disease by a microcytotoxicity assay. Sera from 24 patients (30%) contained LT as judged from at least 50% lysis of lymphocytes from 16 of 23 randomly selected normal donors. The spontaneous incorporation of 14C‐thymidine into blood lymphocytes from patients with LT was significantly higher than that of lymphocytes from LT‐negative patients and from healthy controls. Total lymphocyte and T‐cell counts, Concanavalin A, and pokeweed mitogen‐induced lymphocyte DNA synthesis were lower in patients with LT. Lymphocytotoxic sera were more frequently encountered in patients with B symptoms, advanced disease, or nodular sclerosis/lymphocyte predominance histopathologic characteristics. LT were often found in patients with large and tumor‐involved spleens. The ability of patient'S serum to inhibit control lymphocyte response to Concanavalin A stimulation did not differ between LT‐positive and LT‐negative patients. We conclude that the presence of LT is associated with a quantitative and qualitative impairment of blood T‐lymphocytes in untreated patients with Hodgkin's disease.