PURPOSE: Surgical resection of primary tumor with regional lymphadenectomy remains the treatment of choice for patients with advanced human papillomavirus-negative head and neck squamous cell carcinoma. However, even when pathologic disease-free margins can be achieved, locoregional and/or distant disease relapse remains high. Perioperative immunotherapy may improve outcomes, but mechanistic data supporting the use of neoadjuvant or adjuvant treatment clinically is sparse. EXPERIMENTAL DESIGN: Two syngeneic models of oral cavity carcinoma with defined T cell antigens were treated with PD-1 mAb before or after surgical resection of primary tumors, and antigen-specific T cell responses were explored with functional and in vivochallenge assays. RESULTS: We demonstrated that functional immunodominance developed among T cells targeting multiple independent tumor antigens. T cells specific for subdominant antigens expressed greater levels of PD-1. Neoadjuvant, but not adjuvant, PD-1 immune checkpoint blockade broke immunodominance and induced T cell responses to dominant and subdominant antigens. Using tumors lacking the immunodominant antigen as a model of antigen escape, neoadjuvant PD-1 immune checkpoint blockade induced effector T cell immunity against tumor cells lacking immunodominant but retaining subdominant antigen. When combined with complete surgical excision, neoadjuvant PD-1 immune checkpoint blockade led to formation of immunologic memory capable of preventing engraftment of tumors lacking the immunodominant but retaining subdominant antigen. CONCLUSIONS: Together, these results implicate PD-1 expression by T cells in the mechanism of functional immunodominance among independent T cell clones within a progressing tumor, and support the use of neoadjuvant PD-1 immune checkpoint blockade in patients with surgically resectable carcinomas.