The Cancer Genome Atlas (TCGA) profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Human papillomavirus (HPV)-associated tumors were characterized by helical domain mutations in the oncogene *PIK3CA*, novel alterations involving loss of *TRAF3*, and amplification of the cell cycle gene *E2F1*. Smoking-related HNSCCs showed near universal loss-of-function *TP53* mutations and *CDKN2A* inactivation, along with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumors with favorable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of *HRAS* or *PIK3CA*, coupled with inactivating mutations of *CASP8*, *NOTCH1*, and *TP53*. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier *NSD1*, WNT pathway genes *ALUBA* and *FAT1*, and activation of oxidative stress factor *NFE2L2*, mainly in laryngeal tumors. Therapeutic candidate alterations were identified in most HNSCCs. The study provides a comprehensive integrative genomic analysis of HNSCC, highlighting critical alterations in HPV-associated and smoking-related tumors that may inform new targeted therapies.The Cancer Genome Atlas (TCGA) profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Human papillomavirus (HPV)-associated tumors were characterized by helical domain mutations in the oncogene *PIK3CA*, novel alterations involving loss of *TRAF3*, and amplification of the cell cycle gene *E2F1*. Smoking-related HNSCCs showed near universal loss-of-function *TP53* mutations and *CDKN2A* inactivation, along with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumors with favorable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of *HRAS* or *PIK3CA*, coupled with inactivating mutations of *CASP8*, *NOTCH1*, and *TP53*. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier *NSD1*, WNT pathway genes *ALUBA* and *FAT1*, and activation of oxidative stress factor *NFE2L2*, mainly in laryngeal tumors. Therapeutic candidate alterations were identified in most HNSCCs. The study provides a comprehensive integrative genomic analysis of HNSCC, highlighting critical alterations in HPV-associated and smoking-related tumors that may inform new targeted therapies.