OBJECTIVE With the recent changes in the cause of head and neck cancer and the association of cystic metastatic neck squamous cell carcinoma with human papilloma virus (HPV), patients who are diagnosed with a cystic lesion in their upper neck need thorough investigation before commencing any treatment. RESULTS The differential diagnosis of a cystic mass in the upper neck of an adult over the age of 40 years is a branchial cleft cyst, cystic metastatic squamous cell carcinoma or a branchial cleft cyst carcinoma (BCCC). Investigation must include diagnostic imaging, biopsy or excision biopsy of likely primary sites, such as oropharyngeal sub-sites, and testing for HPV, Epstein-Barr virus immunological status. CONCLUSIONS The existence of BCCC is an exceptional diagnosis, with less than 40 cases considered proven. Consensus agreement has been proposed on making such a diagnosis. The diagnosis of a BCCC should be one of exclusion rather than presumption, after all other possible diagnoses have been considered and excluded.