Background and purpose: This study re-evaluated the prognostic value of HPV status for loco-regional control (LRC), metastases-free survival (MFS), and survival (OS) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). A modified definition of HPV positivity was used in the current study compared to the authors' previous study. Patients and methods: In the previous study of the same 170 patients, a tumor was defined as HPV-positive if it showed a positive in situ hybridization result in ≥ 10 % of tumor cells and/or positive p16 immunostaining. In the current analysis, tumors were considered HPV-positive only if they showed positive results for both in situ hybridization and p16 immunostaining. In addition to HPV status, the same 11 potential prognostic factors were investigated for treatment outcomes as in the preceding study. Results: In the multivariate analysis of the current study, HPV positivity was significantly associated with improved LRC [risk ratio (RR) 9.78; p < 0.001], MFS (RR 7.17; p = 0.008), and OS (RR 6.61; p < 0.001). In the previous study, HPV positivity was associated with LRC (RR 2.34; p = 0.014) and OS (RR 2.19; p = 0.019), but not with MFS (RR 2.04; p = 0.11). Conclusions: Applying the new definition of HPV positivity, the impact of HPV status on the prognosis of patients irradiated for locally advanced SCCHN was more prominent than in our previous study and associated with all three investigated endpoints.