Introduction: Macrolides like azithromycin (AZM) have clinical benefit in the treatment of airway diseases, however, long term treatment with these macrolides promotes antibiotic resistance. Our research on AZM led to the development of the compound EP395 that lacks antibacterial activity but augments epithelial integrity in vitro. In this study we sought to investigate the effect of EP395 on cell diapedesis measured by intravital microscopy in the cremaster muscle of mice. Methods: C57/BL6 male mice were orally treated with 2 mg/kg of EP395 for 14 days. On day 15 all mice received 50?g of zymosan in the scrotal sac and 24 h later prepared for intravital microscopy. Another group was treated with 1 mg/kg of dexamethasone i.p. -24 and -4h prior to zymosan. Results: Zymosan significantly increased cell adhesion to the vascular wall and cell migration into the tissue (saline adhesion: 0.8+0.2; zym adhesion: 8.5+ 0.8*, saline migr. 2.4 + 0.4; zym migr. 20.11 + 2.1* cells counted in 20 sec, p<0.001, n=5). EP395 decreased cell adhesion and significantly inhibited cell migration induced by zymosan (adhesion: 6.5 +0.8, migr:11.7 + 1.1*, cells counted in 20 sec, n=6, p<0.001). Dexamethasone significantly inhibited cell adhesion and cell migration when compared to zymosan (adhesion: 5.2 + 0.5* and migr. 8.7 + 0.9* cells counted in 20s, n=6, p<0.0001) Conclusion: Our data suggest that EP395 alters the transendothelial diapedesis of leukocytes by mechanisms yet to be clarified.