BACKGROUND: Alternatively polarized macrophages (MΦ) shape the microenvironment of hepatocellular carcinoma (HCC) and temper anti-cancer immune responses. We investigated if Sorafenib alters the HCC microenvironment by restoring classical macrophage polarization and triggering tumor-directed NK cell responses. METHODS: In vivo experiments were conducted with Sorafenib (25 mg/kg) treated C57BL/6 wild-type as well as HBV and lymphotoxin transgenic mice with and without HCC. Monocyte derived MΦ or tumor-associated macrophages (TAM) isolated from HCC tissue were treated with Sorafenib (0.07-5.0 µg/ml) and co-cultured with autologous NK cells. MΦ and NK cell activation was analyzed by flow cytometry and killing assays, respectively. Cytokine and growth factor release was measured by ELISA. RESULTS: Short-term administration of Sorafenib triggered activation of hepatic NK cells in wild-type and tumor bearing mice. In vitro, Sorafenib sensitized MΦ to LPS reverting alternative MΦ polarization and enhanced IL12 secretion (P=0.0133). NK cells activated by Sorafenib-treated MΦ showed increased degranulation (15.3±0.2% vs. 32.0±0.9%, P<0.0001) and IFNγ secretion (2.1±0.2% vs. 8.0±0.2%, P<0.0001) upon target cell contact. Sorafenib-triggered NK cell activation was verified by co-culture experiments using TAM. Sorafenib-treated MΦ increased cytolytic NK cell function against K562, Raji and HepG2 target cells in a dose-dependent manner. Neutralization of IL12 or IL18 as well as inhibition of the NFκB pathway reversed NK cell activation in MΦ/NK co-cultures. CONCLUSION: Sorafenib triggers pro-inflammatory activity of TAM and subsequently induces anti-tumoral NK cell responses in a cytokine and NFĸB-dependent fashion. This observation is relevant for HCC therapy, as Sorafenib is a compound in clinical use, which reverses alternative polarization of TAM in HCC.