We aimed to assess the influence of long-term exposure to POPs on the risk of metabolic syndrome, combining a cross-sectional with a 10-year longitudinal follow-up design. Residues of eight POPs were quantified in adipose tissue samples from 387 participants recruited between 2003 and 2004 in Granada province (Spain). The outcome (“metabolically compromised”) was defined as having ≥ 1 diagnosis of type 2 diabetes, hypertension, hypertriglyceridemia, and/or low HDL cholesterol. The cross-sectional analysis was conducted in the initial cohort, while the 10-year longitudinal analysis was conducted in those 154 participants free of any of the so-mentioned metabolic diseases and classified as “metabolically healthy” at recruitment. Statistical analyses were performed using single and multi-pollutant approaches through logistic and Cox regression analyses with elastic net penalty. After adjusting for confounders, β-hexachlorocyclohexane (β-HCH) and hexachlorobenzene (HCB) were independently associated with an increased risk of being metabolically compromised (unpenalized ORs = 1.17, 95% CI = 1.01–1.36 and 1.17, 95% CI = 0.99–1.38, respectively). Very similar results were found in the 10-year longitudinal analysis [HRs = 1.28, 95% CI = 1.01–1.61 (β-HCH); 1.26, 95% CI = 1.00–1.59 (HCB)] and were in line with those obtained using elastic net regression. Finally, when the arithmetic sum of both compounds was used as independent variable, risk estimates increased to OR = 1.25, 95% CI = 1.03–1.52 and HR = 1.32, 95% CI = 1.02–1.70. Our results suggest that historical exposure to HCB and β-HCH is consistently associated with the risk of metabolic disorders, and that these POPs might be partly responsible for the morbidity risk traditionally attributed to age and obesity.