BACKGROUND: In the Middle East and North Africa (MENA), hepatitis C virus (HCV) distribution appears to present a wide range of prevalence. The scale and nature of HCV disease burden is poorly known in the Horn of Africa sub-region of MENA including Djibouti, Somalia, and Sudan in addition to Yemen at the southwest corner of the Arabian Peninsula. The aim of this review is to provide a systematic review and synthesis of all epidemiological data on HCV prevalence and incidence among the different population groups in this sub-region of MENA. A second aim of the study is to estimate the national population-level HCV prevalence for each of these four countries. METHODS/DESIGN: The systematic review will be conducted based on the items outlined in the PRISMA statement. PubMed, Embase, and the World Health organization (WHO) regional databases will be searched for eligible studies without language or date restrictions. Observational and intervention studies reporting data on the prevalence or incidence of HCV in any population group in Djibouti, Somalia, Sudan, or Yemen will be included. Additional sources will be obtained through the database of the MENA HIV/AIDS Epidemiology Synthesis Project, including international organizations' reports and country-level reports, and abstracts of international conferences. Study and population characteristics will be extracted from eligible publications, with previously agreed pro formas; and entered into a computerized database. We will pool prevalence using DerSimonian and Laird random-effects models after a Freeman-Tukey transformation to stabilize variances. We will conduct meta-regression analysis to explore the effect of study-level characteristics as potential sources of heterogeneity. DISCUSSION: This proposed systematic review and meta-analysis aims to better describe HCV infection distribution across countries in the Horn of Africa sub-region of MENA; and between sub-population groups within each country. The study will provide empirical evidence necessary for researchers, policy-makers, and public health stakeholders to set research, policy, and programming priorities for HCV prevention, control, and treatment. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014010318.