B cells play a central role in antiviral and antiparasitic immunity, not only as producers of antibod-ies, but also as APCs and mediators of inflammation. In this study, we used 16-color flow cytom-etry analysis to investigate the frequency, differentiation, and activation status of peripheral Bcells of patientswith SARS-CoV-2 infection or acute Plasmodium falciparum malaria compared withthe healthy individuals. As a main result, we observed an increase of the frequency of (CD27–,CD21–) atypical memoryB cells and (CD19+,CD27+,CD38+) plasmablasts inmalaria and COVID-19 patients. Additionally, CD86, PD-1, CXCR3, and CD39 expression was up-regulated, whereasCD73 was down-regulated on plasmablasts of COVID-19 and malaria patients compared withthe bulk B cell population. In particular, there was a more pronounced loss of CD73+B cells inmalaria. The frequency of plasmablasts positively correlated with serum levels of CRP, IL-6, andLDH of COVID-19 patients. In the longitudinal course of COVID-19, a rapid normalization of thefrequency of atypical memory B cells was observed. The role and function of plasmablasts andatypical memory B cells in COVID-19 and other acute infections remain to be further investigated.The role of B cells as either “driver or passenger” of hyperinflammation during COVID-19 needsto be clarified