Dendritic cells (DC) play a key role in anti-viral immunity. Direct interactions between DC and hepatitis B virus (HBV) may explain the impaired DC function and the ineffective anti-viral response of chronic HBV patients resulting in HBV persistence. Here, the interaction between HBV surface antigens (HBsAg) and DC and the receptor involved were examined by flow cytometry in blood and liver tissue of HBV patients. The in vitro data showed that the mannose receptor (MR) is involved in HBsAg recognition and uptake by DC. The presence of HBsAg-positive DC was demonstrated sporadically in blood, but frequently in the liver of HBV patients. Interestingly, a positive correlation was found between HBsAg positivity and MR expression level in both liver- and blood-derived DC. These data suggest that in HBV infected patients, MR-mediated interaction between HBsAg and DC and subsequent impairment of DC predominantly occurs at the main site of infection, the liver.