Human cytomegalovirus (HCMV) employs multiple mechanisms to evade the immune system and succeeds to persist lifelong in the host. Human dendritic cells (DC) are the main antigen-presenting cells and play the key role in inducing and maintaining immune responses. Here, we studied the interaction of HCMV with DC. We found that DC, irrespectively of their stage of maturation, were fully permissive for HCMV when endothelial cell-adapted HCMV strains were applied. When fibroblast-adapted strains were used, viral replication was abrogated at the level of immediate early (IE) and/or early (E) gene expression. Irrespective of the HCMV strain used, infection of DC prevented the signal delivery essential for T cell activation in a multistep manner. Furthermore, we observed an altered expression of adhesion molecules. This might contribute to an impairment of DC migration. Our data indicate that a soluble factor induced by IE and/or E genes is involved in these processes. The impairment of DC function upon HCMV infection may contribute to virus-mediated immunosuppression and help the virus to establish persistence in the host.