Receptor sites that bind polymerized human serum albumin on hepatitis B virus (HBV) particles were evaluated in purified virus particle preparations and in HBsAg positive sera, by using solid phase radioimmunoassay. The receptor, found in previous reports to be species-specific, was inhibited neither by native human serum albumin, nor by anti-human immunoglobulins or anti-C1q sera, indicating that these host components are not involved in the reaction. Differential receptor expression on various HBsAg particles was evaluated by relating levels of HBsAg to those of polyalbumin binding activity. This ratio was lower in HBsAg particles purified from hepatitis Be antigen (HBeAg) positive serum (mean ratio: 3.5) than in those obtained from anti-HBe positive serum (mean ratio: 20.1), suggesting that HBeAg/anti-HBe status influences the expression of the receptor on virus particles. Accordingly, during acute hepatitis type B receptor activity was high in sera obtained at the onset, but rapidly decreased afterwards, particularly at the time of anti-HBe seroconversion. A similar behavior of the receptor was observed in cases of chronic HBV infection, where mean receptor counts by radioimmunoassay were 3825±4422 (mean cpm ±SD) in HBeAg positive cases and 868±1196 cpm in anti-HBe positive cases ( P<0.01). Seven HBsAg chronic carriers, all initially HBeAg positive, were followed up over a period of 1 to 4 yr and in all of them a progressive decrease in receptor activity was noted, independently of HBeAg persistence. These results indicate that the expression of the receptor for polymerized human albumin on HBV particles is an early event in the natural course of acute and chronic HBV infection, being followed by a progressive reduction in receptor activity, that parallels the reduction in virus replication, often independently of HBsAg serum levels.