Natural cell-mediated cytotoxicity was studied in 18 patients with vitiligo and 13 healthy age-, race-, and sex-matched control subjects. The 4-hour chromium51 (51Cr) release assay was used to determine the activity of natural killer (NK) cells in the peripheral blood against K562 and Molt-4 target cells. Patients with vitiligo had a 50%, 67%, and 60% decrease in the cytotoxic response with Molt-4 cells at effector-target ratios of 25:1, 50:1, and 100:1, respectively, in comparison with control subjects (p less than 0.001). This inhibition was consistent with an 80% decrease in the binding capacity of NK cells to Molt-4 target cells (p less than 0.005). In contrast, cytotoxic responses did not differ in patients and control subjects with K562 target cells. These results suggest that patients with vitiligo have a decreased capacity for effector cell recognition of Molt-4 target cells but not K562 target cells. Hence patients with vitiligo may have defective clones of NK cells that are incapable of initial recognition of Molt-4 target cells, a necessary prerequisite for target cell lysis. Perhaps this phenomenon occurs with other tumor cells, which would explain the association of vitiligo with certain internal malignancies.