Severe acute exacerbation or liver failure induced by standard interferon-α(IFN-α) therapy had been reported to occur in few patients with chronic hepatitis B. However, no report showed that pegylated interferon-α therapy was able to induce severe acute exacerbation of chronic hepatitis B. Here, we describe three patients with severe acute exacerbation of chronic hepatitis B during pegylated interferon-α2a (Pegasys) treatment. Here, IFNA2 is linked to chronic hepatitis B virus infection.