Introduction: Circulating leptin and adiponectin levels have been associated with impaired vascular function, insulin resistance, and acute cardiovascular evens. This study aimed to evaluate the associations of leptin, adiponectin, and the leptin/adiponectin (L/A) ratio with a clustering of metabolic risk factors (MRF) in adolescents aged 12-18 years. Methods: This is a cross-sectional analysis with 529 Portuguese adolescents aged 12-18 years. Blood samples were taken to analyze total cholesterol (TC) and high-density lipoprotein (HDL) cholesterol (HDL-c), triglycerides glucose, insulin, leptin, and adiponectin levels. A continuous variable of clustered MRF score (sum of Z-scores of body fat percentage, systolic blood pressure, ratio TC/HDL, triglycerides, homeostatic model assessment insulin resistance, and cardiorespiratory fitness*[-1]) was computed. Results: Regression analyses showed that adiponectin was a significant and negative predictor of MRF score (boys: ¿ = -0.199; p < 0.001; girls: ¿ = -0.200; p < 0.001); whereas leptin was a significant positive predictor of MRF score (boys: ¿ = 0.553; p < 0.001; girls: ¿ = 0.399; p < 0.001). The L/A ratio was also a significant positive predictor of MRF score in both sexes (boys: ¿ = 0.593; p < 0.001; girls: ¿ = 0.461; p < 0.001), after adjustments for age, pubertal stage, adherence to the Mediterranean diet, and socioeconomic status. In addition, adiponectin, leptin, and L/A ratio were accurate to predict MRF among adolescents, but L/A ratio showed the highest area under receiver operating characteristic curve. Conclusion: Leptin, adiponectin, and L/A ratio are associated with the clustering of MRF in adolescents after adjustments for age, sex, pubertal stage, adherence to the Mediterranean diet, and socioeconomic status. L/A ratio was more strongly associated with MRF score than adiponectin or leptin.