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Background Non-high-density lipoprotein-cholesterol (non-HDL-C) has been identified as a potential biomarker for metabolic syndrome (MetS). However, its predictive capability for MetS varies among different ethnic groups, indicating the need for further clarification. This study aimed to investigate the potential role of non-HDL-C in the early diagnosis of MetS in the Iranian population using a longitudinal study with a 10-year follow-up period.Methods Our study included 4684 individuals from the MASHAD (Mashhad Stroke and Heart Atherosclerotic Disorder) cohort, followed for 10 years to investigate the association between non-HDL-C and the incidence of MetS. We also assessed the contribution of individual components of MetS to the overall burden.Results Out of 7561 individuals, who completed 10-years follow-up, 3085 subjects developed MetS. Non-HDL-C levels ≥ 130 had a 28% higher risk of developing MetS (relative risk (RR),1.27; 95% confidence interval (CI), 1.14–1.41). Elevated waist circumference (WC) had the strongest association with MetS incidence (RR,1.51; 95% CI, 1.45–1.58), whereas triglyceride (TG) levels ≥ 150 mg/dl demonstrated the weakest association (RR,1.07; 95% CI, 1.01–1.15). Fasting blood glucose (FBG) levels ≥ 100 mg/dl were not significantly linked to MetS burden. Conversely, higher HDL-C levels show protective effect against the risk of MetS (RR, 0.87; 95% CI: 0.76-1.00), while blood pressure (BP) levels ≥ 130 mmHg or diastolic BP levels ≥ 85 mmHg increased the risk of MetS incidence (RR, 1.081; 95% CI: 1.037–1.127).Conclusions Elevated non-HDL-C and increased WC are significant predictors of MetS in our population. To reduce the risk of MetS development, strategies targeting non-HDL-C levels and weight loss should be emphasized.