Objective: To investigate the value of serum IgG4 levels in the differential diagnosis of IgG4-related hepatobiliary diseases and other hepatobiliary diseases. Methods: A total of 292 patients with hepatobiliary diseases hospitalized in the People's Hospital of Hunan Province from Au-gust 2017 to August 2018 were enrolled and divided into the following eight groups: the liver cirrhosis group (n=21), acute pancreatitis group (n=56), chronic pancreatitis group (n=42), cholecystitis and gallstone group (n=36), cholangiocarcinoma group (n=28), chol-angitis and cholangiolithiasis group (n=53), pancreatic cancer group (n=39), and IgG4-related hepatobiliary disease group (n=17). In addition, 35 healthy persons were selected as the control group. The level of IgG4 in serum was detected by a rate nephelometry assay. The sensitivity and specificity of IgG4 in the differential diagnosis of IgG4-related hepatobiliary diseases were evaluated using a receiver operating characteristic (ROC) curve. Results: The levels of IgG4 in the cirrhosis group and IgG4-related hepatobiliary disease group were significantly higher than those in the healthy control group (P < 0.05). The level of IgG4 in the liver cirrhosis group, acute pancreatitis group, chronic pancrea-titis group, cholecystitis and gallstone group, cholangiocarcinoma group, cholangitis and cholangiolithiasis group and pancreatic can-cer group was significantly decreased compared with that in the IgG4-related hepatobiliary disease group (Z = -4.984, 7.033, -6.137, -6.332, -6.362, -6.031, -6.524; P < 0.01). The area under the curve (AUC) for IgG4 level in differentiating IgG4-related hepatobiliary diseases from other hepatobiliary diseases was 0.971. When 4.58 g/L was used as the diagnostic threshold point, the sensitivity and specificity values were 92.7 g/L and 91.7 g/L, respectively. The level of IgG4 in 17 patients with IgG4-related hepatobiliary diseases after 3 months of glucocorticoid therapy was significantly lower than that before glucocorticoid treatment (Z = -4.264, P< 0.05). Conclusion: Elevated serum IgG4 is not unique to IgG4-related hepatobiliary diseases. With 4.58 g/L as the diagnostic threshold point, IgG4 is valuable for the differential diagnosis of IgG4-related hepatobiliary diseases and plays a certain role in judging the curative effect after glucocorticoid therapy. However, further detailed verification for these findings is necessary in clinical practice with an expanded sample size.