BACKGROUND Various models of cardiovascular disease that have been used to prove the anti-fibrotic effects of serelaxin. However, whether anti-fibrotic effects of serelaxin are achieved by inhibiting inflammatory response have not been clarified. This research is intended to explore the role of serelaxin in lipopolysaccharide (LPS)-induced inflammation of cardiac fibroblasts (CFs) and elucidated the potential mechanisms. APPROACH Cardiac fibroblasts (CFs) were isolated from the hearts of 3 days neonatal rats. Effects of serelaxin on inhibiting inflammatory response after induction with LPS were examined. Cell proliferation was determined by cell-counting kit-8. The inflammatory cytokines secretion levels of IL-1β, IL-6 and TNF-α, and IL-10 were measured by enzyme-linked immunosorbent assay (ELISA) respectively. The mRNA levels of α-SMA, collagen I/III, MMP-2, MMP-9, IL-1β, IL-6,TNF-α, IL-10, IκBα, p-IκBα, p65 subunit of nuclear factor-kappa B (NF-κB) and peroxisome proliferator-activated receptor-γ (PPAR-γ) were assessed by real-time quantitative PCR (RT-qPCR). The protein levels of α-SMA, collagen I/III, MMP-2, MMP-9, IκBα, p-IκBα, p65, p-p65 and PPAR-γ were examined by Western blotting. RESULTS Serelaxin inhibited LPS-induced IL-1β, IL-6 and TNF-α, α-SMA, collagen I/III, and elevated IL-10, MMP-2 and MMP-9 expression. And, LPS-induced activation of NF-κB pathways was suppressed by serelaxin treatment. Substantially, Further research demonstrated that serelaxin elevated the expression of PPAR-γ and PPAR-γ inhibitor GW9662 could reverse the inhibition of serelaxin on IL-1β, IL-6,TNF-α production. CONCLUSIONS These results suggested that serelaxin alleviates cardiac fibrosis by inhibiting inflammatory products of IL-1β, IL-6 and TNF-α, α-SMA, collagen I/III in LPS-induced CFs by stimulating PPAR-γ which subsequently abolished the expression of NF-κB signalling pathways.