Objectives: (1) To examine whether cardiorespiratory fitness (CRF) is related to liver enzyme levels independent of waist circumference (WC), and (2) To test whether having a high CRF is associated with an improved liver enzyme profile with a high WC. Design: Cross-sectional. Methods: CRF (20 m-shuttle-run test) and WC were assessed in 811 European adolescents (48.5% males) aged 12.5-17.5 years. Fatty liver biomarkers included fasting serum alanine-aminotransferase (ALT), gamma-glutamyl-transpeptidase (GGT) and the aspartate-aminotransferase to ALT (AST/ALT) ratio. Participants were categorized as fit or unfit (CRF below or above 43.8 mL/kg/min and 34.6 mL/kg/min, for boys and girls, respectively) and as high or non-high WC (sex and age-specific cut-offs). Results: CRF was associated with ALT (beta=-0.106; p=0.049) and GGT levels (beta=-0.225; p < 0.001) and AST/ALT ratio (beta=0.234; p < 0.001), yet these relationships were attenuated after further controlling for WC (all p > 0.1). High WC and fit adolescents had lower ALT levels (28 +/- 1 vs. 23 +/- 2 U/L, unfit and fit respectively, p=0.018) and higher AST/ALT ratio (0.94 +/- 0.04 vs. 1.10 +/- 0.06, unfit and fit respectively, p=0.010) than those who were high WC but unfit. Conclusions: The results showed that CRF is not independently associated with liver enzymes, and that WC is a stronger predictor in adolescents. These findings also suggest that high CRF may have specific protective effects on liver enzyme levels in adolescents with high WC. Exercise programs focused on increasing CRF and decreasing abdominal adiposity could be a good alternative in the treatment and prevention of obesity related fatty liver disease in adolescents. (C) 2017 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.