An intronic variant, rs1536036, mapping to ITPR3, a receptor that mediates the release of intracellular calcium, was protective for HNSCC overall (OR (95% CI) = 0.85 (0.80, 0.91), p = 8.42 × 10−7) only in the admixed ancestry. Here, ITPR3 is linked to head and neck squamous cell carcinoma.