Summary This study reports the relationship between CD38+ regulatory T cells (Tregs) and messenger RNA coronavirus disease 2019 (mRNA‐COVID‐19) vaccination in 60 patients with plasma cell dyscrasia. Patients treated with anti‐CD38 monoclonal antibodies (mAbs) had significantly lower CD38+ Tregs than those not treated (0.9 vs. 13.2/μl). Late‐responders, whose antibody titres increased from weeks 4–12 after the second vaccination, had significantly lower CD38+ Treg counts than non‐late‐responders (2.5 vs. 10.3/μl). Antibody titres in patients with lower CD38+ Treg levels were maintained from weeks 4–12 but decreased in those with higher CD38+ Treg levels. Therefore, depletion of CD38+ Tregs by anti‐CD38 mAbs may induce a durable response to mRNA‐COVID‐19 vaccination.