BackgroundBuruli ulcer disease (BUD) caused byMycobacterium (M.) ulceransis characterized by necrotic skin lesions. As for other mycobacterial infections, e.g., tuberculosis, the immune response is important for host protection. B-cells may play a role in antimycobacterial immunity but studies characterizing the B-cell repertoire and memory generation in BUD and during the course of treatment are scarce.MethodsWe investigated the adaptive immune cell repertoire in children with BUD and healthy matched controls by flow cytometry. Analyses prior to treatment, also in a study group of patients with tuberculosis, as well as three time points during BUD treatment (i.e., week 8, 16, and 32) were performed. In addition, BUD disease severity as well as treatment response were analysed for association with B-cell repertoire differences.ResultsChildren with BUD had comparable total B- and T-cell proportions but differed largely in B-cell subsets. Memory B-cell (Bmem) proportions were higher in children with BUD whereas regulatory B-cell (Breg) proportions were lower as compared to healthy controls and tuberculosis patients. Lower naïve (Bnaïve) and higher transitional B-cell (Btrans) proportions characterized children with BUD in comparison with tuberculosis patients. Under treatment, Bmemproportions decreased significantly whereas proportions of Bregand Bnaiveincreased concomitantly in children with BUD. Also, we found significant correlation between lesion size and Bmemas well as Breg. However, we did not detect associations between treatment efficacy and B-cell proportions.ConclusionsThese results suggest a role of B-cell subsets in the immune response againstM. ulcerans. Furthermore, changes in B-cell subset proportions may be used as markers for treatment monitoring in BUD.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12879-023-08370-1.