ABSTRACT— The biological significance of antibody reactivities towards the preS2 gene encoded proteins of HBV is not yet well known. We investigated the pretreatment IgM anti-preS2 (1–55) ad reactivity in 22 Chinese and 11 Swedish patients with active HBV disease. Significantly enhanced IgM anti-preS2 levels (titers >1/1000) were observed in 48% (16/33) of these patients. The OD405 values for sera from patients with indolent HBsAg carriership were within the range of that obtained for “normal” control-sera when tested at dilutions from 1/1000 to 1/128000. Five Chinese patients were treated with a short course of corticosteroids, followed by alpha-interferon 2b (IFN-α2b) treatment for 16 weeks. The IgM anti-preS2 response was consecutively monitored during treatment. A beneficial effect on the outcome of the combined treatment was associated with rising titers of IgM anti-preS2 during the prednisolone cycle. The IgM anti-preS2 levels fell dramatically upon steroid withdrawal and were followed by a second peak response of IgM anti-preS2 reactivity during the IFN-α2b treatment. No sustained loss of HBV-DNA or DNA polymerase with concomitant HBe/anti-HBe seroconversion was observed in treated patients, who lacked detectable pretreatment levels of IgM anti-preS2 in circulation.