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Smokers with squamous cell carcinoma of the head and neck (SCCHN) have a particularly poor prognosis when compared with human papillomavirus-positive SCCHN. Here, we present case reports of two smokers with SCCHN treated with cetuximab-based therapy, highlighting the potential benefit of cetuximab before definitive chemoradiotherapy in patients with poor performance status as well as cetuximab rechallenge after progression. We conclude that cetuximab demonstrated notable effectiveness in two patients at high risk for poor prognosis, yielding a durable response in one and retaining activity on rechallenge in the other.