Objectives: Second primary esophageal squamous cell neoplasms (ESCNs) are common in hypopharyngeal squamous cell carcinoma (HPSCC) patients and are associated with poor prognoses. The effectiveness of image-enhanced endoscopy (IEE) has not been well established. Design: Retrospective study with patients proven HPSCC between April 2016 and April 2018 receiving ESCNs screening via white-light imaging, narrow-band imaging, and Lugol chromoendoscopy. Setting: Data were collected from an electronic medical record at a single medical center in Taiwan. Participants: The study population included a total number of 130 patients with HPSCC receiving ESCNs screening via white-light imaging, narrow-band imaging, and Lugol chromoendoscopy Main Outcome Measures: Clinical data, incidence, and stage of second primary malignancy in HPSCC patients were obtained for statistical comparison. Results: Of 99 eligible patients, second primary ESCNs prevalence was 31%. Of the 69 patients assigned to the follow-up group, 23 with positive findings showed significantly increased previous histories of second primary malignancies in the upper aerodigestive tract. Among them, patients without symptoms at the time of IEE screening showed less advanced T stages and higher percentages of receiving minimally invasive therapy. Conclusions: Routine IEE screening is strongly recommended for HPSCC patients and can improve the detection rate of ESCNs and facilitate early-stage identification.