The interaction of polymerized human albumin with hepatitis B surface antigen was characterized utilizing a solid-phase radioimmunoassay. The interaction was specific as shown by quantitative inhibition of binding by soluble polymerized human albumin. The interaction was species restricted in that hepatitis B surface antigen did not bind nonhuman polymerized albumins. The albumin polymer size was critical to the binding reaction as was the concentration of hepatitis B surface antigen; the interaction was also temperature, ionic strength, and pH dependent. Hepatitis B e antigen positive sera possessed greater polyalbumin binding reactivity than hepatitis B e antigen negative sera. This interaction was shown to be inhibited by normal human serum which suggested that the polyalbumin receptor on hepatitis B surface antigen may be a host rather than viral component. In view of our previous observation that polymerized human albumin binds human C1q, the interactions between polymerized human albumin, hepatitis B surface antigen, and human C1q may be relevant to hepatitis B virus-host receptor mechanisms.