Beside its key diagnostic value, the humoral immune response is thought to play a protective role in hantavirus pulmonary syndrome. However, little is known about the cell source of these antibodies during ongoing human infection. Herein we characterized B‐cell subsets circulating in Andes‐virus‐infected patients. A notable potent plasmablast (PB) response that increased 100‐fold over the baseline levels was observed around 1 week after the onset of symptoms. These PB present a CD3^neg CD19^low CD20^neg CD38^hi CD27^hi CD138^+/− IgA^+/− surface phenotype together with the presence of cytoplasmic functional immunoglobulins. They are large lymphocytes (lymphoblasts) morphologically coincident with the ‘immunoblast‐like’ cells that have been previously described during blood cytology examinations of hantavirus‐infected patients. Immunoreactivity analysis of white blood cell lysates suggests that some circulating PB are virus‐specific but we also observed a significant increase of reactivity against virus‐unrelated antigens, which suggests a possible bystander effect by polyclonal B‐cell activation. The presence of this large and transient PB response raises the question as to whether these cells might have a protective or pathological role during the ongoing hantavirus pulmonary syndrome and suggest their practical application as a diagnostic/prognostic biomarker.