IMPORTANCE: In patients with head and neck squamous cell carcinoma (HNSCC), the discovery of a second synchronous primary cancer of the aerodigestive tract (SSPCA) significantly impacts management and prognosis. Recent advances in imaging have increasingly allowed for identifying SSPCA before performing panendoscopy, raising questions about the latter's role. OBJECTIVE: To establish the incidence of SSPCA and panendoscopy's impact on management. Complications and costs associated with panendoscopy were also assessed. DESIGN: Systematic review following the preferred reporting items for systematic reviews and meta-analysis guidelines. SETTING: Operating room panendoscopy. PARTICIPANTS: Identifiable HNSCC undergoing initial staging workup. INTERVENTION: Panendoscopy under general anesthesia for SSPCA detection. MAIN OUTCOME MEASURES: Incidence of SSPCA in HNSCC, change in management caused by panendoscopy, incidence of panendoscopy complications, costs for panendoscopy. RESULTS: 51 studies were included (n = 19,914 patients). SSPCA was present in 6.4% (n = 467/7262) of all panendoscopies. Among patients who had a prior computed tomography (CT) of the neck and chest, a change in management resulting from SSPCA detected through panendoscopy occurred in only 1.1% of cases (n = 3/268), and in 0% of cases for those who had a positron-emission tomography-computed tomography (PET) (n = 0/544). The rate of major complications of panendoscopy was 0.7% (n = 58/8386). Only two recent studies in a private healthcare system reported panendoscopy costs ranging from 802 USD to 7,296 USD. CONCLUSIONS: The role of panendoscopy in the initial workup of HNSCC should be limited to confirming suspicious findings from initial CT or PET. The incidence of major complications for panendoscopy is low but carries a significant financial burden for patients in the private American healthcare system. More studies are needed to assess the cost-effectiveness of panendoscopies for SSPCA detection in a public healthcare system. RELEVANCE: Confirms the lack of benefit for systematic panendoscopy for SSPCA detection in HNSCC patients when initial workup includes a CT of the neck and chest or PET.