Background: The East African corridor is uniquely home to the highest concentrations of both esophageal cancer cases and HIV infections in the world. Objective: To investigate the relationship between HIV infection parameters such as CD4 count and ARV compliance and the development of esophageal cancer in this highly endemic area. Methods: Based on the PRISMA-P 2015 guidelines, this protocol has been written. We will systematically search Web of Science, African Journals Online, Embase, Scopus, Cochrane Library, and Medline/PubMed for relevant literature. Studies with esophageal cancer as an outcome, and HIV status as an exposure, will be considered eligible. Standards tools will be used in the quality assessment process. Egger's statistical test and funnel plots visualization will be used to assess for potential publication bias. Separate reviewers will choose the studies, gather data, and assess each included study's risk of bias. GRADE method will be used to assess the degree of certainty in the evidence, and RevMan 5.4 and Stata 17.0 will be used for the meta-analysis. Although the East African corridor has the highest number of people living with both HIV and esophageal cancer in the world, the level of association between these two diseases remains unknown. Ethics and dissemination: This study will comprehensively evaluate the available data on the subject to establish the possible links that exist between EC and HIV infection, to inform clinical practice on the need to strengthen disease surveillance and future research. Review registration: PROSPERO CRD42023473775.