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High-grade serous carcinoma (HGSC) of the ovary remains the deadliest gynecologic cancer, with 5-year survival rates of less than 50%. Remission is usually achieved by surgical debulking and chemotherapy, but most (∼70%) of patients ultimately develop treatment-resistant disease. Infiltration of immune cells into the HGSC microenvironment, including natural killer (NK) cells, is associated with lengthened overall and progression-free survival, suggesting that immunosurveillance contributes to HGSC control. The mechanisms permitting or prohibiting anticancer activity are unclear, but if understood, they might shed light on opportunities for immunotherapy or precision medicine. We investigated the interactions between NK cells and adenosine, an immunosuppressive metabolite that concentrates in HGSC. Exposure of HGSC to adenosine induces upregulation of ligands associated with NK cell inhibition, including HLA-E. On NK cells, adenosine induces upregulation of the cognate inhibitory receptor for HLA-E, natural killer group 2A (NKG2A). The CD16low NK cell subset was most responsive to the HGSC cell line, OVCAR4, but also more likely to upregulate NKG2A and become inhibited after adenosine treatment. A single nucleotide polymorphism (SNP) in the gene for NKG2A (V5: rs2734440 C) encodes for higher NKG2A surface expression and a stronger inhibitory response to HLA-E-expressing targets. Here, we demonstrate that NK cell suppression in the context of adenosine is most profound in NK cells homozygous for the V5 variant. Our results reveal a novel link between metabolism and immunologic inhibition and highlight the KLRC1-V5 variant as a putative biomarker for response to anti-NKG2A therapy and/or susceptibility to adenosine-driven immunosuppression.