Chlamydia pneumoniae, a gram-negative obligate intracellular bacterium, is a common cause of upper and lower respiratory tract infections worldwide. Persistent C. pneumoniae infections have been linked to chronic disease processes, such as atherosclerosis. In the present study, we examined gene expression changes in the human epithelial cell line at different stages of acute C. pneumoniae infection and used gene ontology annotation, along with single-gene analysis, to select a small group of target genes that could possibly play a key role in C. pneumoniae infection. Selected genes were silenced using small interfering RNA, and the effect of silencing on the number of C. pneumoniae inclusions was measured by time-resolved fluorometric immunoassay. The greatest reduction in the number of C. pneumoniae inclusions was due to the silencing of the gene coding for the transcription factor early growth response 1, which decreased the number of inclusions by 38.6%.