© 2020 Tsukuda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Introduction Some patients with IgG4-related disease (IgG4-RD) exhibit elevated serum interleukin (IL)- 6 with excessive inflammatory reactions or with repeating relapse. To date few reports pertaining to clinical implications of elevated serum IL-6 in IgG4-RD patients have been published. The aims of the current retrospective study were to investigate the clinical implications of elevated serum IL-6 in IgG4-RD patients, and to examine whether IL-6 can predict the activity and/or relapse of the disease. Materials and methods We examined the clinical picture at the onset of 43 patients who were diagnosed with IgG4- RD in our hospital and were able to measure serum IL-6 before steroid treatment. Results The median level of serum IL-6 was 2.2 pg/mL. There was a significant correlation between IL-6 and C-reactive protein (CRP) level (r = 0.397, p = 0.008), hemoglobin level (r = -0.390, p = 0.010) and albumin level (r = -0.556, p < 0.001). When 43 patients were divided into two groups by using a cut-off IL-6 of 4 pg/mL, the high IL-6 group showed higher age, lower albumin, higher CRP and higher aspartate aminotransferase (AST) (age p = 0.014, albumin p = 0.006, CRP p <0.001, AST p = 0.009). Hepatic swelling and splenomegaly were significantly more prevalent in the high IL-6 group than it was in the low IL-6 group (liver p < 0.001, spleen p = 0.020). Biliary tract involvement tended to admit more in the high IL-6 group (p = 0.060). Conclusion Serum IL-6 level at the onset of IgG4-RD may be significantly correlated with clinical inflammatory parameters and it may also be associated with involvement of the bile duct, liver, and spleen.