To study the relationship of cold-reactive lymphocytotoxic antibodies (LCA) to immune defects in cancer, LCA were measured in sera from 71patients with different types of malignancies and 31 healthy controls. A significantly increased incidence (10 of 24) of LCA was noted in a group of patients with lymphoreticular malignancies excluding chronic lymphocytic leukemia (CLL). No significantly increased incidence of LCA was found in patients with CLL (0 of 9), melanoma (5 of 22), or carcinoma (1 of 16) as opposed to normal controls (1 of 31). In the lymphoreticular malignancy group, no correlation was noted between LCA levels and delayed hypersensitivity skin tests, skin croton oil response, total lymphocytes, T cells, or B cells. We conclude that LCA is increased in patients with certain lymphoreticular malignancies in contrast to other types of cancer. Its presence, however, is unrelated to major defects in the cell-mediated immune system seen in some of these patients.