The HNK-1 (Leu-7) monoclonal antibody was used to enumerate and characterize the level of blood granular lymphocytes in 247 cancer patients. The results were compared to 146 control individuals. A fluorescence-activated cell sorter was used to purify blood HNK-1+ cells from cancer patients. The monoclonal antibody identified a homogeneous population of granular lymphocytes with greater than 95% purity. Conversely, virtually 100% of HNK-1- cells from cancer patients were agranular lymphocytes. These results were the same as previously observed in normal individuals, where the HNK-1+ cell fraction contained all the lymphocytes with spontaneous cytotoxicity in natural killer (NK) and killer (K) cell assays. The level of HNK-1+ cells in cancer patients correlated significantly with the patient's age and sex, with older individuals having higher levels and male patients containing a higher proportion than female patients. The levels in the cancer patients were significantly lower than normal controls (p = 0.04). When the results were subdivided by the histologic type of cancer, additional differences were noted. Compared to age and sex-matched controls, significantly depressed levels of HNK-1+ granular lymphocytes were observed in 49 patients with colon cancer (9.7% vs. 15.8%, p = 0.0001), 18 patients with lung carcinoma (11.7% vs. 27.0%, p = 0.0001), 24 patients with breast carcinoma (12.0% vs. 15.5%, p = 0.04) and 64 patients with head and neck carcinoma (15.9% vs. 19.1%, p = 0.05). However, there were no significant differences overall in the average HNK-1+ cell level of 66 patients with melanoma (13.0% vs. 13.5%, p = 0.75) and nine patients with sarcomas (15.8% vs. 14.3%, p = 0.71). Thus, this important subpopulation of granular lymphocytes with NK and K cell function was significantly depressed in most cancer patients. Accounting for the patient's age and sex and the histologic type of cancer was critical to interpreting the results.