Abstract: Objective To investigate the role of receptor-interacting protein 140 (RIP140) in tumor-associated macrophages (TAMs) in the invasion and proliferation of hepatoma cells in vitro. Methods Western blotting, qRT-PCR and flow cytometry were performed to examine the effects of lentivirus-mediated RIP140 over-expression in mouse peritoneal macrophages (PMs). Western blotting, qRT-PCR and immunofluorescence staining were used to detect the expression of RIP140 in TAMs following stimulation of the PMs with hepatocellular carcinoma conditioned medium (HCM) for 24 h. The polarization index and the expression of NF-κB and IL-6 were detected using qRT-PCR in TAMs in HCM-stimulated PMs with or without RIP140 over-expression. Transwell assay and flow cytometry were used to estimate the cell invasion and apoptosis. HE staining and immunohistochemical staining were used to analyze the effects of RIP140-over-expressing macrophages on the growth and tumor formation of H22 cells in BALB/c nude mice. Results The lentivirus vector efficiently mediated RIP140 over-expression in mouse PMs. HCM stimulation significantly inhibited RIP140 expression in the TAMs and promoted their M2-like polarization. Over-expression of RIP140 in PMs suppressed the invasion and induced apoptosis of HCC cells. RIP140 over-expression inhibited HCM-induced M2 polarization and the activation of NF-κB/IL-6 axis in the TAMs, and RIP140- overexpressing TAMs obviously suppressed the growth of H22 cell xenograft in nude mice. Conclusion Over-expression of RIP140 in TAMs suppresses the growth and proliferation of hepatoma cells possibly by inhibiting M2 polarization of the TAMs.