The effect of PD-1 blockade as a first-line therapy in nonmetastatic head and neck squamous cell carcinoma (HNSCC) remains unknown. We report a case of an exceptional response to PD-1 blockade as a first-line therapy in a patient with HNSCC and lung cancer. A 59-year-old man presented with cheek swelling and chest pain. He was diagnosed with maxillary sinus carcinoma (squamous cell carcinoma) and lung cancer (non-small-cell lung cancer, not otherwise specified). The maxillary sinus carcinoma was completely resolved after 8 cycles of pembrolizumab. Immune checkpoint blockade warrants further evaluation in previously untreated patients with HNSCC.