Background: Worldwide, Human Immunodeficiency Virus / Acquired Immunodeficiency Syndrome (HIV/AIDS) remains a public health concern. The prevalence of HIV in Sub-Saharan Africa is one of the uppermost in the world. This study aims to identify the determinants of morbidity and specific causes of mortality in the antiretroviral treatment (ART) era in Sub-Saharan Africa.Method/design: Observational studies will be systematically reviewed reporting on morbidity and mortality in the antiretroviral therapy (ART) era in Sub-Saharan Africa. We will search for relevant studies from Google Scholar, PubMed, and CINAHL databases. Two review authors will independently screen titles, abstracts and full-text articles in duplicate, extract data and assess the bias. Discrepancies will be resolved by discussion or arbitration of a third review author. The study will use the Preferred Reporting Item of Systematic Review (PRISMA 2015) guideline. We will use R software to analyze and synthesize the data, the information will be captured into a spreadsheet regarding the most causes of hospitalization and death related to HIV in the antiretroviral treatment, Graphic displays will be used to visually compare the prevalence of comorbidities across the study region. This will also enable to provide any form of patterns in the comorbidities.Discussion: This review will summarize the determinants of morbidity and causes of mortality in the antiretroviral era in Sub-Saharan Africa. The findings of this study will help to improve opportunistic infection’s prevention and clinical outcomes in the ART era.Systematic review registration: PROSPERO CDR42019141933