Nasopharyngeal cancer (NPC) is traditionally EBV related. However, HPV-positive (HPV+) NPC seems to be increasing in the Western world recently. We describe the clinical behavior and outcomes of HPV+ NPC compared to EBV-positive (EBV+) NPC and HPV+ oropharyngeal cancer (OPC).All newly diagnosed non-metastatic viral-related NPC and OPC treated with IMRT from 2005-2020 were reviewed. Viral etiology was confirmed by p16 staining, supplemented by real-time polymerase chain reaction of DNA for high-risk HPV, and EBER in-situ hybridization for EBV. Clinical characteristics of HPV+ and EBV+ NPC were compared using the 2005-2020 NPC cohort, while locoregional control (LRC), distant control (DC) and overall survival (OS) were compared using the 2005-2018 cohort to allow sufficient follow-up among HPV+ NPC, EBV+ NPC and HPV+ OPC patients. Presenting signs/symptoms of HPV+ NPC and EBV+ NPC were compared by 1:1 matched pair analysis (matched to T category, N category, smoking, age, gender, WHO type IIA vs IIB, and diagnosed year). Multivariable analysis (MVA) evaluated the cohort effect adjusting for confounders.A total of 29 HPV+ NPC (25 Caucasians and 4 Asians), 422 EBV+ NPC, and 1310 HPV+ OPC were eligible. HPV genotype was available in 20/29 HPV+ NPC patients: 14 (70%) HPV-16; 6 (30%) non-HPV-16. Compared to EBV+ NPC overall, HPV+ NPC patients were older (median age: 58 vs 52 years, P = 0.006), were predominantly Caucasian (86% vs 15%, P < 0.001), and had higher T (T2-4: 86% vs 68%, P = 0.039) but similar N categories (N2-3: 66% vs 58%, P = 0.44). Within the matched cohort, more HPV+ NPC patients complained of local pain vs EBV+ NPC (28% vs 3%, P = 0.025) but a similar proportion had cranial neuropathy (21% vs 31%, P = 0.55). No significant difference existed in gross tumor volume or involved lymph node distribution (P > 0.05). Median follow-up for HPV+ NPC, EBV+ NPC and HPV+ OPC was 3.1, 6.0, and 5.2 years respectively. Compared to EBV+ NPC (n = 374), HPV+ NPC (n = 20) had similar 3-year LRC (95% vs 90%, P = 0.416) and OS (84% vs 89%, P = 0.137), but non-significantly lower DC (75% vs 88%, P = 0.13). Compared to HPV+ OPC (n = 1310), HPV+ NPC also had similar 3-year LRC (95% vs 94%, P = 0.74) and OS (84% vs 87%, P = 0.307), but lower DC (75% vs 90%, P = 0.036). The difference in DC became non-significant in MVA [HR 1.83 (0.73-4.58), P = 0.19] after adjusting for T category, N category, smoking pack-years, and chemotherapy.HPV+ NPC is an emerging entity, of which about one-third are caused by non-HPV-16 genotype. Compared with the more common EBV+ NPC cases, HPV+ NPC presents with more local pain and advanced T categories but has similar outcomes. HPV+ NPC also has similar outcomes to HPV+ OPC except that DC is lower in univariable analysis, possibly attributable to higher T category and non-HPV-16 genotypes. There may be a role for modification of systemic therapy in HPV+ NPC to address distant failure risk.