Metabolic syndrome (syndrome X, MetS) is a multifactorial disease with multiple risk factors that arises from insulin resistance accompanying abnormal adipose deposition and function (Olufadi and Byrne, 2008). MetS was described by Reaven in 1988 as the co-occurrence of insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia and hypertension (Reaven, 1988). MetS is linked to a higher risk of type 2 diabetes mellitus (T2DM) as well as cardiovascular diseases (CVDs). Disorders of lipid and lipoprotein metabolism are linked to the development of these pathologies. Dyslipidemia causes an excess of potentially atherogenic lipids and lipoproteins to be produced. Moreover, the levels of high-density lipoprotein (HDL) decrease while the levels of low-density lipoprotein (LDL) increase (Iqbal et al., 2017). Fructose is a simple monosaccharide that has been used as a sweetener in food and drinks (Le and Tappy, 2006). The increase in consumption of fructose is closely related to the incidence of obesity (Bray et al., 2004). Fructose-mediated MetS may be induced in male Sprague-Dawley/Wistar/Albino rats by feeding them a high-fructose diet (20–66%) or by adding fructose (10–20%) to their drinking water (Mamikutty et al., 2014). The major goal of treating MetS is to reduce the risk of CVDs including raising LDL-C and reducing HDL-C, high blood pressure and abdominal fat (Kaur, 2014). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein that aids in cholesterol homeostasis by enhancing hepatic low-density lipoprotein receptor degradation. PCSK9 is produced primarily in the liver and intestine, where it controls the expression and function of LDLR and LDL homeostasis (Mbikay et al., 2013). The consistent findings that PCSK9 directly correlates with levels of triglycerides (TGs), glucose metabolism, and insulin resistance paved the way for its potential role in the MetS (Ferri and Ruscica, 2016). Noteworthy, despite being mainly produced and secreted by the liver, PCSK9 is also expressed in other organs and cell types including the intestine, kidneys, adipocytes, pancreatic β cells, macrophages, and vascular smooth muscle cells. This suggests that PCSK9 may exert a variety of biological function beyond the control of LDL metabolism, namely pleiotropic effects (Bittner, 2016). Accordingly, PCSK9 appears to have a function in immunologic response, glucose metabolism, hemostasis, neuronal survival, and several other biological functions (Seidah, 2016). PCSK9 has been linked to many glucose metabolism indices, including fasting plasma glucose, insulin and IR homeostasis model (HOMA-IR) (Ferri and Ruscica, 2016). The first anti- PCSK9 monoclonal antibodies, alirocumab and evolocumab, were approved by the United States Food and Drug Administration in 2015 to treat patients with hypercholesterolemia and mixed dyslipidemia (Sabatine et al., 2015). Therefore, the aim of the present study is to investigate the effect of evolocumab on cardio-metabolic disorders in male albino rats with fructose-induced metabolic syndrome and to demonstrate its possible mechanism of action.