Hepatic fibrosis (HF) is a pathological process in many liver diseases, which lack of specific agents. Pirfenidone (PFD) derivatives are potential new drug. The purpose of this study was to investigate the effect and immunological mechanism of PFD derivatives on HF. A total of 11 PFD derivatives were designed, synthesized and screened. 1-benzyl-6-nitro-4-phenyl-4-(methoxycarbonyl)-2(1 H)-pyridinone (code: Compound 5) had optimal effect on inhibiting nitric oxide release, hepatic stellate cells (HSCs) and T cell proliferation, which suggested that Compound 5 showed anti-inflammatory, anti-fibrosis and immunoregulation effects. Compound 5 inhibited the proliferation of HSC-T6 and T cell in dose-dependent manner, the IC