Background: HRAS is significantly mutated in head and neck squamous cell carcinomas (HNC) and is a putative oncogenic driver. We studied the impact of HRAS mutations and signaling, which remains poorly defined for HNSCC. Methods: We evaluated HRAS expression, copy number changes, and hotspot mutations in HNSCC tumor tissues and cell lines (Chicago HNC Genomics Cohort (CHGC) (N=120), HNC TCGA (N=279), and HNC cell lines (N=50). MAPK, PI3K-AKT pathway signaling was interrogated by immunoblotting, and viability/apoptosis were determined in HRAS mutant and control cell lines (HN4(G12D), BB49(Q61L) and H357(G13S)) in presence of EGFR, and/or PI3K inhibitors. Results: Incidence of HRAS mutations was 4% in CHGC and TCGA cohorts, and 6.1% in HNC cell lines – with almost exclusively canonical HRAS mutations. Neither HRAS expression nor copy number aberrations were associated with mutations, and no high-level CN aberrations occurred. HRAS siRNA gene knockdown was extremely effective at inducing apoptosis and decreased viability in all three HRAS mutated cell lines, but largely ineffective in control cell lines. Interestingly immunoblotting revealed that mutant HRAS signals exclusively via PI3K-AKT and not via the MAPK pathway. EGFR inhibition had no visible effect on viability or apoptosis in these cell lines, and did not impact PI3K pathway activity. By contrast PI3K inhibition was highly effective and induced apoptosis. Combinations of PI3K and EGFR inhibition showed synergy only in wild-type cell lines. Lastly we developed HRAS mutation gene expression signature that confirmed PI3K signaling dependence. By contrast HRAS wildtype co-expression modules enrich for EGFR and MAPK signaling. Conclusions: Canonical HRAS mutations are strong oncogenic drivers and in-vitro associated with high-level EGFR-resistance. Unlike KRAS in other tumor types, HRAS in HNC signals exclusively via the PI3K pathway, and PI3K inhibitors are effective at inducing apoptosis and decreased viability.