Background: Definitive radiotherapy with concurrent cisplatin (CDDP) is a standard treatment for patients (pts) with LAHNSCC. We evaluated the impact of CDDP dose intensity (mg/m²) on overall survival (OS) of HPV+ and HPV- LAHNSCC pts. Methods: Princess Margaret Cancer Centre (PM) and Istituto Nazionale dei Tumori (INT) LAHNSCC cohorts treated from 2000 to 2012 were reviewed. Kaplan-Meier method was used to estimate the 5-year (yr) OS in HPV+ vs HPV− pts. HPV status was determined by p16 staining or in situhybridization HPV DNA for all oropharyngeal (OPC), unknown primary (UNK), and ≤ 10 pack-year (PY) smoking laryngo-hypopharyngeal cancer (LHC). Untested p16, >10 PY LHC pts were assumed HPV−. Multivariable analysis (MVA) with Cox regression identified OS predictors for HPV+ and HPV− pts. Results: A total of 659 pts (584 PM; 75 INT) were evaluated. Pts characteristics included: median age 58 (range: 27-81); primary site: OPC 73%, LHC 24%, UNK 3%; non-smokers 27%; stage: T4 25%, N2c-N3 60%; HPV+ 404 (61%), HPV− 255 (39%) pts. Median CDDP dose was 200 mg/m² for both HPV+ and HPV− cohorts. Median follow-up was 4.3 yrs. Five year OS was inferior for HPV− CDDP ≤ 200 vs > 200 mg/m² (44 vs 62%, p < 0.01), while no difference was detected in HPV+ CDDP ≤ 200 vs > 200 mg/m² (83 vs 87%, p = 0.30), confirmed by MVA (Table). In N3 or T4 HPV+ pts, a trend on OS in CDDP >200 mg/m²(HR = 0.62, 95% CI: 0.30-1.31) was observed. Conclusions: In this large multicenter cohort study, CDDP dose intensity ≤ 200 mg/m²had a detrimental impact on OS in HPV− LAHNSCC pts. The impact of CDDP dose intensity on HPV+ pts was not significant. These results warrant prospective validation.