Background: Patients with squamous cell carcinoma of the head and neck (HNSCC) have an increased risk of developing a second primary tumor (SPT), most frequently in the head and neck, lung and esophagus. The development of an SPT has impact on choice of treatment and survival. Patients with HNSCC therefore undergo a comprehensive staging and work-up regime, which traditionally has included panendoscopy. With the evolvement of better technology, computed tomography (CT) and positron emission tomography (PET) are now widely available, and the need of routine panendoscopy is questioned. The purpose of this review is to evaluate if there is evidence in the literature whether routine bronchoscopy and esophagoscopy can be replaced by radiological techniques. It should also try to evaluate whether work-up in patients with HPV-positive HNSCCs should be different than that of patients with HPV-negative HNSCC. Methods: An extensive literature search in PubMed and The Cochrane Library was conducted to identify studies describing the utility of either panendoscopy, bronchoscopy, esophagoscopy, CT or PET in detecting SPTs among patients with HNSCC, either alone or in comparison with one or several of the other examination methods. Guidelines from Denmark (DAHANCA), the United Kingdom and National Comprehensive Cancer Network (NCCN) were also reviewed. Results: Several studies showed that CT, PET or PET/CT have a better sensitivity than bronchoscopy in detecting SPTs in the lung, and several of the guidelines and studies recommended chest CT for all patients with newly diagnosed HNSCC. The reviewed literature recommended esophagoscopy in patients at high risk for developing an SPT of the esophagus, with the sensitivity of imaging modalities in detecting early esophageal carcinoma being too low. Several studies showed a lower SPT-risk for patients with HPV-positive HNSCC. Conclusion: The role of panendoscopy in staging of HNSCC is still contentious. According to the reviewed literature, routine bronchoscopy can probably be replaced by routine CT of the chest. Esophagoscopy is still recommended for patients with index tumor of the hypo- or oropharynx, or a history of chronic alcohol abuse. Based on the reviewed literature, it is still too early to change the work-up regime for patients with HPV-positive HNSCC.