Background and aims: Several cross-sectional, but few prospective, studies suggest that inflammation may be involved in the development of high blood pressure. We examined markers of inflammation for their associations with blood pressure levels over a two-year period in healthy adolescents. Methods and results: The sample comprised 406 adolescents (209 girls) aged 12–18 years in the LabMed Physical Activity Study were followed-up for 2 years. Anthropometric (weigh, height, BMI), markers of inflammation (high sensitivity C-reactive protein, complement factors C3 and C4, fibrinogen, leptin and adiponectin) and ambulatory blood pressure (BP) were collected. Socioeconomic status, pubertal development, adherence to Mediterranean diet and cardiorespiratory fitness were measured for adjustment for potential confounders. Adjusted linear regression models revealed a significant association of Leptin/Adiponectin (L/A) Ratio (baseline) with systolic BP (β = 0.120; p < 0.034) and with diastolic BP (β = 0.125; p < 0.036) at follow-up (full adjusted model). Leptin was associated with systolic BP at follow-up (β = 0.102; p < 0.038) after adjustment for systolic BP at baseline, height, pubertal stage, socioeconomic status, adherence to Mediterranean diet, cardiorespiratory fitness, however, not independently of BMI. Conclusion: L/A ratio was positively associated with systolic BP and diastolic BP even after adjusting confounding variables. Therefore, a higher misbalance between leptin and adiponectin (higher L/A ratio) early adolescence may exert a negative effect BP levels in late adolescence regardless of several confounders factors.