Abstract Objectives Head and neck squamous cell carcinoma (HNSCC) is a complex malignancy that requires a multidisciplinary tumor board approach for individual treatment planning. In recent years, artificial intelligence tools have emerged to assist healthcare professionals in making informed treatment decisions. This study investigates the application of the newly published LLM Claude 3 Opus compared to the currently most advanced LLM ChatGPT 4.0 for the diagnosis and therapy planning of primary HNSCC. The results were compared to that of a conventional multidisciplinary tumor board; (2) Materials and Methods: We conducted a study in March 2024 on 50 consecutive primary head and neck cancer cases. The diagnostics and MDT recommendations were compared to the Claude 3 Opus and ChatGPT 4.0 recommendations for each patient and rated by two independent reviewers for the following parameters: clinical recommendation, explanation, and summarization in addition to the Artificial Intelligence Performance Instrument (AIPI); (3) Results: In this study, Claude 3 achieved better scores for the diagnostic workup of patients than ChatGPT 4.0 and provided treatment recommendations involving surgery, chemotherapy, and radiation therapy. In terms of clinical recommendations, explanation and summarization Claude 3 scored similar to ChatGPT 4.0, listing treatment recommendations which were congruent with the MDT, but failed to cite the source of the information; (4) Conclusion: This study is the first analysis of Claude 3 for primary head and neck cancer cases and demonstrates a superior performance in the diagnosis of HNSCC than ChatGPT 4.0 and similar results for therapy recommendations. This marks the advent of a newly launched advanced AI model that may be superior to ChatGPT 4.0 for the assessment of primary head and neck cancer cases and may assist in the clinical diagnostic and MDT setting.