Human head and neck squamous cell carcinoma (HNSCC) is highly prevalent with approximately 890,000 new diagnosed cases and 450,000 deaths annually. Lack of early detection and high tumor metastasis, recurrence, and drug resistance account for such overwhelming numbers. Unfortunately, routinely used two-dimensional cancer cell cultures are not biologically relevant model systems to accurately study patient tumors. In this work, we sought to test and develop the hamster cheek pouch as a potential HNSCC patient-derived xenograft (PDX) model system. Donor tumor tissue from HNSCC patients were transplanted into hamster cheek pouches. Tumor volumes were measured over 4-6 weeks by performing weekly post-transplantation assessments of the xenotransplantation sites. Cheek pouches with viable transplanted masses were excised from hosts after 4-6 weeks for tissue harvesting and processing. We assessed both donor tissues and viable xenotransplants using standard histological and immunohistochemical analyses of formalin-fixed and paraffin-embedded tissue preparations. Although transplanted tumors generally regressed over time, these tumors did persist long-term without immunological rejection. The hamster cheek pouch model also showed maintenance of histopathological characteristics between donor tumor tissue and viable xenografts. However, protein expression and localization lacked routine replication. While statistical analyses supported our observation that the hamster cheek pouch does initially accept the implantation of HNSCC patient tumor tissues, it also revealed that differential aspects among patient tumor tissue did not significantly effect tumor viability. However, an inherent variability among individual cheek pouch sites were observed. Further studies are needed to refine the hamster cheek pouch as a potential HNSCC PDX model system so as to discover and validate diagnostic biomarkers, prognostic predictors, and therapeutic treatments.