Objective To investigate the serum level of fibroblast growth factor 21 (FGF21) and its relation with insulin secretion in simple obesity patients with acanthosis nigricants. Methods A total of 35 obese patients (OB group) and 38 obese patients with acanthosis nigricants (AN group) visiting our department were included in this study, and 20 age-matched healthy volunteers were taken as controls. The lipid profile, free fatty acid (FFA), uric acid (UA) and C-reactive protein (CRP) were measured in each group, and the glucose tolerance and insulin secretion were also observed in all participants. Serum FGF21 level was measured by ELISA. Results Acanthosis nigricants was associated with more severe hyperinsulinemia and insulin resistance in obese patients. The levels of FGF21, fasting insulin and homeostasis model of assessment for insulin resistance (HOMA-IR) in AN group were significantly higher than those in the OB and control groups (P<0.05,P<0.01), while the insulin activity index (IAI) of AN was significantly lower than those in the OB and control groups (P<0.01). Correlation analysis showed that serum FGF21 level was positively correlated with fasting insulin and HOMA-IR (r=0.410, P=0.009;r=0.350, P=0.027), while negatively correlated with IAI and body fat percentage (r=-0.615, P<0.001; r=-0.554, P<0.001). Logistic analysis showed that higher level of FGF21 and UA were the independent risk factors for AN in obese patients(P=0.008, P=0.020). Conclusion Obese patients with AN have high serum FGF21 level and hyperinsulinemia, and increased FGF21 level is associated with insulin resistance. Obese patients with AN have a slighter impaired glucose tolerance than simple obese patients, suggesting that increased FGF21 may benefit glycometabolism. Higher FGF21 and uric acid are the independent risk factors for AN in obese patients.