OBJECTIVE To identify biomarkers for disease activity in IgG4-related disease (IgG4-RD) and primary Sjögren's syndrome (pSS). METHODS Forty-three consecutive treatment-naïve patients with IgG4-RD, 62 patients with pSS, and 5 patients with sicca syndrome were enrolled. IgG4-RD and pSS disease activity was assessed based on the IgG4-RD responder index (IgG4-RD RI) and EULAR Sjögren's Syndrome Disease Activity Index (ES- SDAI), respectively. The associations of biomarkers with disease activity were examined. RESULTS Comparison of the three dis- eases identified the serum levels of IgG, IgG4, IgG4/IgG ratio, IgE, and soluble interleukin-2 receptor (sIL-2R) for IgG4-RD and the serum levels of IgM and sIL-2R and lymphocyte counts for pSS as potential biomarkers of disease activity. Among these, serum sIL-2R levels correlate with baseline IgG4-RD RI scores and the number of affected organs in IgG4-RD (ρ=0.74, p<0.0001 and ρ=0.75, p<0.0001, respectively). Serum sIL-2R levels also correlate with ESSDAI scores and the number of af- fected organs in pSS (ρ=0.67, p<0.0001 and ρ=0.41, p<0.0001, respectively). Receiver operating characteristic curve analysis suggested serum sIL-2R levels as an efficient biomarker to distinguish the presence of extra-dacryosialadenitis involvements in IgG4-RD with a cut-off value of 424 U/mL (AUC=0.93, p<0.0001), and in pSS with 452 U/mL (AUC=0.89, p<0.0001). Serum sIL-2R levels decreased significantly after treatment in patients with IgG4-RD and pSS. CONCLUSIONS Serum sIL-2R levels are a potentially valuable biomarker for evaluating disease activity and treatment response in IgG4-RD and pSS.