Introduction: Previous studies have hypothesized fibroblast growth factor 21 (FGF-21) as a potential biomarker of the inflammation associated with liver diseases, which is also receiving considerable attention for its potential application concerning the management of obesity and co-morbidities. This study aimed to analyze the response of FGF-21 after a weight loss intervention and the relationships with other putative inflammatory liver biomarkers. Material and methods: Sixty-six obese participants from the RESMENA study were evaluated at baseline and following a 6-month energy restriction treatment. Anthropometric, body composition by DXA, routine laboratory measurements, which included transaminases and -glutamyl transferase (GGT) were analyzed by standardized methods. Moreover, FGF-21, M30 fragment (M30) and plasminogen activator inhibitor-1 (PAI-I) were analyzed as recognized liver inflammatory related biomarkers with specific ELISA kits. Results: Most measurements related to hepatic damage, inflammation and adiposity status improved at the end of the 6-month nutritional intervention. In addition, ΔFGF-21 shifts showed statistical relationships with changes in ΔM30, ΔGGT and ΔPAI. The reduction of M30 showed significant associations with changes in transaminases. Furthermore, PAI-I changes were associated with ΔM30 and ΔGGT regardless of weight loss. A linear regression model was set up to assess the influence of ΔPAI-I and ΔM30 on the variability of ΔFGF-21 (23.8%) adjusted by weight loss. Conclusions: These results demonstrated interactions of some liver inflammatory mediators, specifically M30 and PAI-I with FGF-21. Thus, more investigation about FGF-21 is required given that this protein could be a biomarker of the obesity-inflammation-liver process.