Introduction: Azithromycin (AZM) is widely used in the treatment of airway diseases, but it?s long-term and off label use contributes to the development of antimicrobial resistance.  Research on AZM led to the development of the compound EP395, an anti-inflammatory macrolide derivative that lacks antibacterial activity.  In this study, we sought to investigate the effect of EP395 on the resolution of peritoneal inflammation induced by zymosan. Methods: C57/BL6 mice received 5 mg of zymosan i.p. and 72 h later received a single p.o. dose of 33 mg/kg of AZM, or 33 or 100 mg/kg of EP395. The peritoneum was lavaged 4 h later. All mice received 100 µl of Evans Blue dye immediately after administration of the drugs (EB, 0.5% solution i.v.). Results: Zymosan significantly increased neutrophil numbers (saline: 0+0.0; Zym: 3.1+0.4* x 10⁶/ml, p<0.001, n=10). EP395 significantly decreased the number of neutrophils at 100 mg/kg, (100 mg: 1.4+0.5*, 33mg: 2.5+0.6 x 10⁶/ml, n=10/group, p<0.01). Measured by flow cytometry, EP395 significantly decreased the percentage of M1 macrophages population in the peritoneal lavage induced by zymosan (zym: 1.7+0.5; 100mg/kg: 0.7 + 0.2; 33 mg/kg 0.6 + 0.2 %, n=10). EP395 at 100 mg/kg significantly inhibited the extravasation of EB into the peritoneal cavity vs. zymosan alone (Zym: 6.4±1.4; EP395: 2.8±0.4* µg/ml, n=10/group, p<0.01). Conclusion: Our data suggest that EP395 accelerates the clearance of neutrophils, decreases pro-inflammatory M1 macrophages and inhibits vascular permeability induced by zymosan in the peritoneal cavity of mice.