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Human cytomegalovirus (HCMV) infection suppresses cellular immunity and results in viral persistence. Dendritic cells (DCs) are susceptible to HCMV, and the development and immune function of HCMV-infected DCs are impaired in vitro. HCMV-derived proteins interfere with different aspects of major histocompatibility complex type II (MHC II) maturation and function in genetically engineered cellular models. This study directly analysed the effect of HCMV on the MHC II-associated antigen processing and presentation machinery in HCMV-infected human DCs in vitro. HCMV-infected DCs failed to mature newly synthesized MHC II to the final stage of SDS-stable MHC II alphabeta dimer/peptide complexes, in contrast to mock-infected controls. MHC II biosynthesis was delayed and reduced, whilst MHC II stability remained unchanged. MHC II surface expression was decreased in the late phase of HCMV infection. In addition, infected DCs decreased the transcription rate of the MHC II-associated proteases cathepsins S, Z, B, H and L and asparagine-specific endopeptidase (AEP). This translated into reduced protein expression of cathepsins H and S, as well as AEP, and less-efficient proteolytic degradation of a peptide substrate by endocytic proteases from HCMV-infected DCs in vitro. Thus, HCMV infection interferes with MHC II biosynthesis and maturation, as well as with the expression and function of endocytic proteases in infected DCs.