In addition to tube drains, pleural empyema is treated with antibiotics and anti-inflammatory drugs. We aimed to evaluate the anti-inflammatory activity of roflumilast combined with linezolid in a rat model of pleural empyema induced by Staphylococcus aureus.A total of 40 rats were separated into 7 groups: Sham (n=4), S. aureus inoculation (n=6), S. aureus + 10 mg/kg linezolid (n=6), S. aureus + 5 mg/kg roflumilast (n=6), S. aureus + 10 mg/kg linezolid+5 mg/kg roflumilast (n=6), S. aureus + 10 mg/kg roflumilast (n=6), and S. aureus + 10 mg/kg linezolid + 10 mg/kg roflumilast (n=6). Linezolid was administered 1 hour before and 12 hours after inoculation with S. aureus. Roflumilast was administered orally as a single dose 30 minutes before inoculation with S. aureus. Compared to linezolid alone, linezolid combined with 5 mg/kg roflumilast provided statistically significant improvement in TNF-alpha, IL-1 beta, vasodilation/congestion, and tissue/pleural PNM infiltration (p<0.05).Linezolid combined with 10 mg/kg roflumilast also provided statistically significant improvement TNF-alpha, IL-1 beta, IL-6, endothelin-1, vasodilation/congestion, mesothelial cell damage, lung tissue PNL, and pleural PNL compared to linezolid alone (p<0.05).Due to its anti-inflammatory effect and significant impact on recovery, roflumilast can be used in conjunction with antibiotherapy for the treatment of pleural empyema.