Objective <p>Head and neck cancer (HNC) has achieved improved locoregional control; however, long-term survival remains compromised by the development of multiple primary malignancies (MPM). This study aimed to investigate the clinical patterns of multiple primary malignancies involving HNC in a 20-year single-institution cohort from East Asia.</p> Patients and methods <p>We retrospectively reviewed 86 patients diagnosed with multiple primary malignancies, including HNC, between 2004 and 2024. To assess subsite-specific associations, 104 cancer pairs were analyzed by matching each HNC with each non-HNC on a one-to-one basis. This approach accounted for 12 patients with three primary malignancies and two patients with four primary malignancies.</p> Results <p>Lung (24.0%), colorectal (15.3%), and gastric cancers (13.4%) were the most frequently associated malignancies. Thyroid cancer was the most common HNC subsite (24.0%); however, hypopharyngeal cancer demonstrated the highest normalized prevalence of multiple primary malignancies (3.5%) and showed significant associations with gastroesophageal tumors. Additionally, a significant association was observed between oral cavity cancer and hematologic malignancies, with the hematologic malignancy preceding the oral cavity cancer in all five cases. Metachronous tumors were more prevalent than synchronous tumors, with a mean interval of 46.9 months following the diagnosis of the index cancer. Synchronous malignancies occurred more frequently when HNC was the index tumor (<i>p</i> = 0.0068).</p> Conclusion <p>Significant subsite-specific associations are observed between hypopharyngeal and gastroesophageal cancers, as well as between oral cavity and hematologic malignancies. Metachronous tumors predominate over synchronous tumors, occurring at a mean interval of 46.9 months following the diagnosis of the index cancer.</p>