AIMS: Patients with obesity and insulin resistance are at higher risk for arterial and venous thrombosis due to a prothrombotic state. If this is reversible by lifestyle intervention was addressed in the current study and potential underlying associations were elucidated. SUBJECTS AND METHODS: One-hundred individuals with impaired glucose tolerance or impaired fasting plasma glucose participated in a 1-year lifestyle intervention, including precise metabolic phenotyping and MRT-based determination of liver fat content as well as a comprehensive analysis of coagulation parameters before and after this intervention. RESULTS: During the lifestyle intervention significant reductions in coagulation factor activities (II, VII, VIII, IX, XI and XII) were observed. Accordingly, prothrombin time (PT%) and activated partial thromboplastin time (aPTT) were slightly decreased and prolonged, respectively. Moreover, PAI-1, vWF and also protein C and protein S decreased. Fibrinogen, antithrombin, D-Dimer and FXIII remained unchanged. Searching for potential regulators, especially weight loss, but also liver fat reduction, improved insulin sensitivity and decreased low-grade inflammation were linked to favorable changes in hemostasis parameters. INDEPENDENT OF WEIGHT LOSS: , liver fat reduction (FII, protein C, protein S, PAI-1, vWF), improved insulin sensitivity (protein S, PAI-1) and reduced low-grade inflammation (PT%, aPTT, FVIII/IX/XI/XII, vWF) were identified as single potential regulators. CONCLUSIONS: Lifestyle intervention is able to improve a prothrombotic state in individuals at high-risk for type 2 diabetes. Besides body weight, liver fat content, insulin sensitivity and systemic low-grade inflammation are potential mechanisms for improvements in hemostasis and could represent future therapeutic targets.