Objectives: The aim of the present systematic review was to identify the factors that potentially influence health-related quality of life (HRQoL) in women with breast cancer (BC) in the Middle East. Methods: A systematic search of the PubMed, Ovid Medline, Cochrane, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, and Ebscohost databases was conducted to identify all relevant articles published in peer-reviewed journals up to April 2018. The keywords were "Health related quality of life", "Breast Cancer", and "Middle East countries". The Newcastle-Ottawa (NOS) scale was used to evaluate the methodological quality of the included studies. Due to the methodological heterogeneity of the identified studies, no statistical pooling of the individual effect estimates was carried out; instead, the results were summarized descriptively. Results: A total of 5668 articles were screened and 33 studies were retained. The vast majority of these studies were cross-sectional and only two were longitudinal prospective studies. Concerning the methodological quality, only 39% were of high quality. Our comprehensive literature review identified several modifiable and non-modifiable risk factors associated with HRQoL, including sociodemographic, clinical, and treatment-related factors as well as behavioral and psychosocial factors. Conclusion: This study has many implications for clinical practice and may provide a framework for establishing policy interventions to improve HRQoL among women with BC. Healthcare systems in the Middle East are encouraged to develop interventional programs targeting modifiable factors, particularly socio-demographic, behavioral, and psychosocial factors.The Middle East is a region located in western Asia and extends into North Africa, with an estimated population of over 411 million. It comprises 15 countries with different ethnic groups holding different cultures, norms, and beliefs. Although BC incidence rates are lower in the Middle East compared to other western societies, they have substantially increased over the last few decades [1]. According to GLOBOCAN estimates, approximately 119,985 (34.2%) new BC cases and 48,661 (24.9%) cancer-related deaths occurred in 2018 [1]. Furthermore, a large proportion of women are diagnosed with BC at younger age, i.e., under 40 years old, and at an advanced stage, where BC is generally aggressive and requires mastectomy [2]. In most countries of the Middle East, BC is still considered a sensitive and taboo topic, surrounded by shame and silence. Most Middle Eastern societies mention it as "that other disease" and many women are petrified to talk about it [3]. The perception of BC as incurable and its fatality are also a concern. Therefore, a diagnosis of BC can be a devastating event and can expose Middle Eastern women to a high burden of psychological suffering that could adversely affect their health-related quality of life (HRQoL).According to Osoba et al., HRQoL is "a multidimensional construct that includes perceptions of b...