Background: Immunoglobulin G4-related disease (IgG4-RD) promptly responds to glucocorticoids but relapses in a considerable fraction of patients. Reliable biomarkers of flare are currently lacking because the pathophysiology of IgG4-RD remains largely elusive. In the present work, we aimed to identify perturbations of B-cell subpopulations that might predict IgG4-RD relapse. Methods: Thirty patients were treated with glucocorticoids according to international guidelines. Circulating CD19+and CD20+cells, naive B cells, memory B cells, plasmablasts, and plasma cells were measured by flow cytometry at baseline and every 6 months for 2 years after the initiation of corticosteroid therapy. Results: Patients with active untreated IgG4-RD showed significantly reduced CD19+B cells, CD20+B cells, and naive B cells compared with healthy subjects (p <0.05), but significantly expanded plasmablasts and plasma cells (p <0.01). After 6 months of corticosteroid treatment, all patients achieved clinical improvement. Naive B cells, plasmablasts, and plasma cells significantly decreased compared with disease onset, whereas memory B cells significantly increased compared with baseline (p <0.01). Increase of memory B cells was observed only in patients who relapsed within 2 years of follow-up, however (HR, 12.24; 2.99 to 50.2; p = 0.0005). In these patients, the relapse rates at 12 and 24 months were 30% and 100%, respectively. No abnormalities of other B-cell subpopulations at disease onset or after 6 months of glucocorticoid treatment were found to predict IgG4-RD relapse at 2 years. Conclusions: Increase of circulating memory B cells after 6 months of glucocorticoid treatment might predict IgG4-RD relapse. © 2018 The Author(s).