Background Endotrophin is the cleavage product COL6. Recent findings indicate that endotrophin is actively involved in inflammation, angiogenesis, and fibrosis. It also seems to play a critical role in obesity-induced systemic insulin resistance by increasing chronic inflammation and fibrosis in adipose tissues. In this study, we aimed to reveal the relationship between human adipose tissue, inflammation, and insulin resistance (IR). Methods The study included 51 IR patients and 37 healthy controls. The presence of IR was based on Homeostatic model of assessment-insulin resistance (HOMA-IR) level of 2, 7, or higher. Fasting plasma samples were obtained from the patients and the control group. Results The IR patients had a higher HOMA-IR, waist circumference, fasting plasma glucose (FPG), fasting insulin (FI), and triglyceride levels than the control subjects (p < 0.05). Endotrophin and CRP levels were significantly higher in patients with IR than controls (23.12 +/- 18.32 ng/mL; 11.20 +/- 6.60 ng/mLp < 0,001; 5.5 +/- 3.37 ng/L; 1.97 +/- 0.89 ng/Lp < 0.001). The serum endotrophin level showed a positive correlation with HOMA-IR (r = 0.359;p < 0.001), waist circumference (r = 0.214; p < 0.05), FI (r = 0.386;p < 0.001), and CRP level (r = 0.251;p < 0.05) Conclusion The serum endotrophin level was higher in patients with IR, independently of BMI, fasting glucose, and all other factors. Therefore, we foresee that high levels of endotrophin may be a new biomarker for early diagnosis of metabolic worsening in overweight and obesity. We also found a positive correlation between endotrophin and CRP. This indicates that endotrophin is closely related to inflammatory processes.