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Purpose/Aims This study focused on delineating the possible effects of roflumilast (ROF), a selective phosphodiesterase 4 (PDE4) inhibitor, in rats with cecal ligation and puncture (CLP)-induced polymicrobial sepsis, and investigated whether ROF can act as a protective agent in sepsis-induced lung damage. Material and methods Four experimental groups were organized, each comprising eight rats: Control, Sepsis, Sepsis + ROF 0.5 mgkg−1, and Sepsis + ROF 1 mgkg−1 groups. A polymicrobial sepsis model was induced in the rats by cecal ligation and puncture under anesthesia. Twelve hours after sepsis induction, the lungs were obtained for biochemical, molecular, and histopathological analyses. Results In the sepsis group’s lungs, the TNF-α, IL-1β, and IL-6 mRNA expression levels peaked in the sepsis group’s lung tissues, and ROF significantly decreased these levels compared with the sepsis group dose-dependently. ROF also significantly decreased MDA levels in septic lungs and increased antioxidant parameters (SOD and GSH) compared with the sepsis group. Histopathological analysis results supported biochemical and molecular results. Conclusions ROF, a PDE4 inhibitor, suppressed the expression levels of pro-inflammatory cytokines, alleviated lung damage (probably by blocking neutrophil infiltration), and increased the capacity of the antioxidant system.