A feature of the large outbreak of human enterovirus 71 (EV71)-associated hand-foot-and-mouth (HFMD) disease in China in 2008 was that severe cases presented with encephalitis. This study was performed to evaluate the immunophenotypic characteristics of patients with neurological involvement. Twenty-one patients with encephalitis and 14 with uncomplicated HFMD were recruited. Age-matched healthy volunteers were enrolled as controls. Peripheral lymphocyte subsets were analyzed by use of 3-colour flow cytometry, and the quantitative determination of plasma immunoglobulin (Ig) levels was also monitored. Comparisons between severe and mild cases demonstrated significant elevations of B cells and IgG levels and corresponding general decreases in natural killer (NK) cells and T lymphocytes in severe cases at the acute stage of infection (p < 0.01 for all). During the convalescent phase, rapid recoveries of B cells and IgG to the normal levels were observed, which appeared to be accompanied by an increase in EV71-specific neutralizing antibody titres. In summary, our data demonstrate that elevated B cells and IgG might be associated with neurological manifestations in EV71 infection.