Tight junction (TJ) proteins, which form cell‐to‐cell contacts, play a central role in maintaining the integrity of the blood‐brain barrier (BBB) and brain homeostasis. Acute phase proteins (APP) are elevated in chronic inflammatory diseases but their effects in BBB function and structure have not been investigated.The objective of this study was to examine the effects of APPs on an in vitro BBB model using rat brain microvessel endothelial cells (RBMEC). Following treatment with APPs, culture supernatant and protein were collected. The following methods were used in our study: enzyme‐linked immunoabsorbant assay (ELISA) to measure cytokines, Western blot analysis for TJ protein expression, and immunohistochemistry for TJ protein localization. Additionally, RBMEC permeability following APP treatment was measured.Results from this study showed a significant increase of TNF‐α in the supernatant following treatment with α‐1‐acid glycoprotein (AGP). Increased permeability was seen with AGP treatment while serum amyloid A treatment induced decreased permeability. Our immunohistochemistry results showed a decrease in claudin‐5 expression following haptoglobin treatment.In summary, our results show that APPs have direct effects on BBB function and TJ protein localization. This suggests that APPs may play a role in altering BBB integrity in chronic inflammatory diseases.Funded by: NHLBI, R15‐HL092561