The induction of antibody-dependent cellular cytotoxicity (ADCC) through FcγRIIIa (CD16) is a hallmark NK cell activation pathway being exploited for immunotherapeutic applications. A common human CD16 polymorphism, 158V (allelic frequency of 0.42 by Ensembl), significantly increases binding affinity for IgG Fc and potentiates ADCC relative to 158F. Consequently, 158V/V homozygous cancer patients exhibit better clinical response to ADCC-inducing therapeutic antibodies. However, other natural CD16 variants are less well characterized. We report that CD16 L48H (0.12 frequency) and L48R (0.06 frequency) variants both significantly enhance in vitro ADCC responses in NK-92 cells and primary NK cells (48L/H or 48L/H compared to 48L/L). We also found that CD16 48H formed a more compact immunological synapse interface, more robust intracellular calcium signaling, and quicker polarization of cytolytic vesicles. During ADCC responses, NK cells expressing CD16 48H exhibited more rapid ADAM17-dependent disengagement from target cells during ADCC than those expressing CD16 48L, resulting in improved serial killing. In addition, we recently found that NK cells expressing the L48H/R polymorphisms are surprisingly resistant to exhaustion after overnight exposure to ADCC conditions. Whereas NK cells from CD16 48L/L donors exhibited low capacity for additional ADCC and co-expressed TIGIT and TOX, NK cells from heterozygous 48L/H or 48L/R donors were still highly functional and lacked these biomarkers. The protection from exhaustion was partially abrogated when 48-H/R-expressing NK cells were treated with ADAM17 inhibitors during the overnight ADCC. Distinct gene expression signatures were also observed between NK cells expressing the different CD16 variants after overnight ADCC. Taken together, the CD16 L48H/R polymorphisms have potential to benefit patient responses to cancer antibody therapies and may also enhance anti-tumor ADCC responses if incorporated into adoptive NK cell therapeutic platforms. Supported by NIH grants U01-AI148117, T32-CA9035, and CCSG-CA06927.