Chlamydophila pneumoniae alter the expression of Toll-like receptor (TLR) 4 in alveolar type II (ATII)-cells. Subsequently nuclear factor kappaB (NF-κB) is activated and tumor necrosis factor-α (TNF-α) and macrophage inflammatory protein 2 (MIP-2) are produced. Perfluorocarbons (PFC) are beneficial in animals with bacterial pneumonia and reduce production of TNF-α. Using isolated ATII-cells, it was studied whether PFC prevent C. pneumoniae-induced TNF-α and MIP-2 release and what the underlying pathway is. PF5080 preincubation prevented C. pneumoniae-induced secretion of TNF-α (43 ± 10 versus 661 ± 41 pg/mL) and MIP-2 (573 ± 41 versus 4786 ± 502 pg/mL). The C. pneumoniae-induced 2.2-fold increase of TNF-α Receptor 1 expression was reduced by PF5080. C. pneumoniae reduced cytoplasmatic IκBα (3.7 ± 0.3 versus 14 ± 1) and increased NF-κB p65 (31 ± 7.5 versus 3.6 ± 1.1) compared with control. PF5080 prevented NF-κB activation. TLR4 expression was 1.5-fold higher after C. pneumoniae incubation, but remained at control levels after PF5080 pretreatment. After 24 h of C. pneumoniae incubation, in 88 ± 6% of cells bacteria were found in the perinuclear region and in 50% of these cells bacteria adhered to cellular surface. After PF5080 preincubation, C. pneumoniae were in 32 ± 4% attached to and in 5 ± 1% internalized in ATII-cells. Since PF5080 was found in ATII-cell membranes, PF5080 effect could be explained by an alteration of the cellular membrane, preventing activation of the inflammatory cascade.