Importance Innovative clinical trials (CTs) are needed to address the rising incidence of head and neck squamous cell carcinoma (HNSCC). Despite adequate trial initiation, HNSCC CTs experience high failure rates, and the factors driving these trends remain unclear. Objective To assess the characteristics associated with failure (termination or withdrawal) in CTs for the treatment of HNSCC. Design and Setting HNSCC CTs were identified on ClinicalTrials.gov from January 1, 2000, to December 31, 2024, and trial failures were defined as early termination or withdrawal. Trial characteristics were compared between failed CTs and completed CT controls. Data were analyzed from June to August 2025. Main Outcomes and Measures The primary outcome was trial failure. The association between failure and CT characteristics, including phase, enrollment, funding source, intervention type, and age-eligibility criteria, was analyzed using descriptive statistics and multivariable regression models. Results A total of 692 matched trials were analyzed, including 346 trial failures and 346 completed control trials. The overall leading reasons for failure were strategic decisions (defined as nonscientific, sponsor-driven choices; 102 trials [29.5%]) and poor recruitment (90 trials [26.0%]). The reasons for failure varied by trial characteristics. Strategic decisions were the predominant reason for failure in phase 1 trials, industry-sponsored trials, and immunotherapy and targeted therapy trials. In contrast, poor recruitment was a more common reason in later-phase trials, non–industry-sponsored trials, and trials investigating chemotherapy, radiation, chemoradiation, combination treatments, and supportive care. Temporal analysis revealed a growing failure rate among CTs since 2000. Increased log-transformed actual enrollment safeguarded against trial failure, whereas industry funding was an independent risk factor. Conclusions and Relevance In this study, HNSCC CTs were terminated early or withdrawn for a variety of reasons, most commonly due to strategic decisions or poor recruitment. Careful attention to trial characteristics associated with early failure is needed to overcome new barriers to drug development and adapt trial design to common reasons for failure.