Background: Worldwide despite the availability of antiretroviral therapy, human immunodeficiency virus/acquired immunodeficiency syndrome still causes morbidity and mortality among patients. In Sub-Saharan Africa, human immunodeficiency virus/ acquired immunodeficiency syndrome remains a major public health concern. The aim of this study was to identify the causes of morbidity and mortality in the modern antiretroviral therapy era in Sub-Saharan Africa.Methods: We conducted a systematic review according to the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. We searched relevant studies from 3 databases which are Google Scholar, PubMed, and CINAHL. Two review authors independently screened titles, abstracts, and full-text articles in duplicate, extracted data, and assessed bias. Discrepancies were resolved by discussion or arbitration of a third review author. R software version 3.6.2 was used to analyze the data. Maximum values were used in order to show which disease was mostly spread out by looking at the highest prevalence reported. This systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO).Results: A total of 409 articles were obtained from the database search, finally 12 articles met the inclusion criteria and were eligible for data extraction. Among them, 3 were conducted in Nigeria, 2 were conducted in Uganda, 3 were conducted in South Africa, 1 in Gabon, 1 in Ethiopia, 1 in Ghana, and 1 in Burkina Faso. In most of the included studies, tuberculosis was the leading cause of hospitalization which accounted for between 18% and 40.7% and it was also the leading cause of death and accounted for between 16% and 44.3%, except in 1 which reported anemia as the leading cause of hospitalization and in 2 which reported wasting syndrome and meningitis respectively as the leading causes of death. Opportunistic malignancies accounted between for 1.8% to 5% of hospitalization and 1.2% to 9.8% of deaths.Conclusions: Tuberculosis is the commonest cause of hospitalization and death in Sub-Saharan Africa, but it is always followed by other infectious disease and other non-AIDS related causes.Abbreviations: ART = antiretroviral therapy, CD4 = cluster of differentiation 4, HIV/AIDS = human immunodeficiency virus/ acquired immunodeficiency syndrome, Q2 = median, PICO = population, intervention, comparator and outcome, PLHIV = patients living with HIV, PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses, UKZN = University of KwaZulu-Natal.