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Background: Several studies have linked metabolic syndrome (MetS) to osteoarthritis (OA), but they have not looked into how MetS can affect the health-related quality of life (HRQOL) of OA individuals. Objectives: We aimed to assess the association of MetS and its components, including obesity, hypertension, hyperglycemia, and dyslipidemia, with HRQOL among Egyptians with knee OA. Methods: This cross-sectional study comprised 116 adult Egyptian participants with knee OA. They were divided into 2 groups based on whether or not they had the MetS. All participants were subjected to a thorough medical history taking and a detailed medical examination. The Kellgren and Lawrence (K/L) scale evaluated OA in all individuals using anteroposterior knee radiographs. The Health Assessment Questionnaire-Disability Index (HAQ-DI) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were used to assess participants' HRQOL; their higher scores indicate more disability. Spearman rank and Pearson's correlation analyses were used to assess the association between variables. Results: Diabetes, hypertension, dyslipidemia, and obesity were significantly associated with the OA + MetS group with a prevalence of 77.6%, 82.8%, 77.6%, and 50.0%, respectively. According to the K/L scale, 70.7% of the OA + MetS group had grade IV knee affection. The HAQ-DI and WOMAC scores were significantly (P <.001) higher among the OA + MetS individuals compared with the OA individuals. Interleukin (IL)-6 serum levels were also significantly higher in the OA + MetS group (P =.036) and increased significantly with the more serious radiological damage and functional disability. We found significant positive correlations between HAQ-DI and WOMAC with waist circumference (P =.004,.001), as well as triglycerides (P =.006,.008), cholesterol (P =.041,.048), fasting blood sugar (P <.001, <.001) and significant negative correlations with high-density lipoprotein levels (P =.628,.002). Conclusions: Individuals with knee OA with MetS showed more significant radiological damage, severe functional disability, and poor HRQOL. They also had higher levels of IL-6, which correlated significantly with the degree of disability, promoting it as a significant therapeutic target. [ABSTRACT FROM AUTHOR]