Abstract In this manuscript, we demonstrated that following stimulus by Kupffer cell-conditioned medium (KCM) and PDGF-BB, hepatic stellate cells (HSCs) showed significant increases in DNA synthesis and PDGFR-β expression. Furthermore, phosphorylation of PDGFR-β and three major members of the mitogen-activated protein kinase (MAPK) family were also significantly increased. Studies with respective neutralizing antibodies against released cytokines in conditioned medium demonstrated that PDGF-BB played an essential role in this complex activation process. Administration of A771726, leflunomide’s metabolite, markedly blunted these effects. However, the combination of A771726 with any of the three MAPK inhibitors potentiated this inhibitory effect and showed completely blockage on PDGFR-β expression and phosphorylation. Collectively, these data demonstrate that leflunomide inhibits KCM-mediated HSC proliferation via PDGFR-β phosphorylation and the subsequent activation of the MAPK pathway. Accordingly, targeted intervention against the PDGF-BB isoform may also offer a promising therapeutic approach to liver fibrosis.