The intracellular pathogen Chlamydia trachomatis diversely interacts with its host cell in order to complete growth and to form progeny. In the present study, the major histocompatibility complex I (MHCI) antigen presentation pathway was examined during active and persistent infection in order to find out whether or not C. trachomatis interferes with this pathway dependent on its growth state. The results showed that active C. trachomatis infection of epithelial cells leads to degradation of the TAP2 subunit of the transporter of antigen presentation, which correlated with abnormal MHCI trafficking and reduced MHCI cell surface expression. Further, it was found that this manipulation of the MHCI antigen presentation did not occur during IFN- γ mediated persistent infection and fibroblast infection, which was used as another host cell model. Additionally, C. trachomatis growth in fibroblasts was characterized, which revealed a new type of chlamydial persistence in these cells that differed substantially from the IFN-γ induced persistence. Further, the functional MHCI pathway during persistent infection correlated with a reduced expression of an important chlamydial protease secreted into the host cytosol, which is necessary for cleavage of host proteins in order to manipulate host cell functions. Also, degradation of some host proteins only occurred during active, but not during persistent infection. Altogether, the results suggest that the ability of Chlamydia to interact with host cell pathways, such as the MHCI antigen presentation pathway, largely depends on host cell types that promote productive chlamydial growth and thus expression of chlamydial effector proteins. An interference with the MHCI presentation pathway during active C. trachomatis infection may reduce recognition through cytotoxic T cells and thus represent a mechanism to escape the host immune response in order to ensure growth and reproduction.