Current evidence indicates that natural killer (NK) cells, which are large granular lymphocytes that mediate non-major histocompatibility complex (MHC)-restricted cytotoxicity and antibody-dependent cytotoxicity and that are involved in multiple regulatory, developmental, and immunologic processes, are important in health. Immunodeficiency states presenting with low NK activity are often associated with malignancies, chronic viral infections, or autoimmune diseases. Monitoring of NK function appears to be indicated as an aid to diagnosis, prognosis, and follow-up after therapy. Reliable performance of NK assays in a clinical laboratory requires that uniform criteria be established and followed for the acceptability of results. Statistical analysis of daily variability can be of great assistance in identifying and tracking sources of error, but routine statistical adjustments are not generally advisable. The quality control program described here provides a degree of assurance that this cytotoxicity assay can be dependable whether performed at one time point or serially. The successful implementation of this program requires laboratory resources, biostatistical support, and interpretative skills, all of which are available in a modern clinical laboratory.