Chlamydophila pneumoniae and Chlamydia trachomatis cause infections of the respiratory or urogenital tract. In addition, both species have been associated with atherosclerosis or reactive arthritis respectively. For these intracellular pathogens the interaction with their host-cells is of particular importance. To get insight into this relationship, we conducted a comparative analysis of the host-cell gene regulation of human epithelial cells during infection with Chlamydia. In a screening of HeLa cells by Affymetrix-microchips, numerous regulated host-genes were identified. A detailed expression profile was obtained for 14 genes by real-time RT-PCR - comparing C. pneumoniae, C. trachomatis and intracellular S. typhimurium. The transcriptional responses induced by C. pneumoniae were similar (but usually smaller) compared to C. trachomatis, some were absent. UV-inactivated bacteria induced no differential gene expression suggesting that pathomechanisms other than those associated with innate immunity play here an important role. The expression pattern induced by Salmonella differed substantially. These genus- or group-specific transcriptional response patterns elicited by viable intracellular pathogens may considerably contribute to the different pathologies encountered in the clinic.