The relation between preS1 antigen/antibody system and different phases of hepatitis B virus infection were studied in 425 serum samples from 50 hepatitis B patients before, during and after antiviral therapy using interferon alone or in combination with corticosteroid withdrawal. A typical profile of self-limited acute hepatitis B was characterized by hepatitis B virus-DNA clearance using polymerase chain reaction and preS antigens using monoclonal radioimmunoassays and by antibody responses to the middle and the large HBs proteins (gp33/gp36 and p39/gp42) using immunoblotting quantitative analysis. After interferon therapy in patients with protracted hepatitis B, complete eradication of the virus was observed in 70% of patients, and antibody response directed to middle HBs and large HBs proteins could be induced. Conversely, this antibody response was never detected in follow-up studies of chronic active hepatitis B patients who responded well to antiviral therapy and lost HBs, preS2 and preS1 antigens. Most interesting, in 50% of patients with HBeAg-positive chronic active hepatitis B who received combination therapy and in 67% of patients with anti-HBe-positive chronic active hepatitis B given interferon alone, the elevated serum preS1Ag/HBsAg ratio persisted after treatment was discontinued and even increased until the end of the follow-up when hepatitis B virus DNA was undetectable in serum by the conventional hybridization technique. This rebound of preS1 antigen expression following antiviral therapy in patients with chronic active hepatitis B may indicate virus persistence, suggesting the possibility of relapse through wild-type hepatitis B virus or the emergence of hepatitis B virus mutants.