PURPOSE Current treatments for metastatic RCC (mRCC) do not extend survival beyond a few months. Sorafenib (SF) is a targeted drug approved for mRCC, but it has modest efficacy. Hymecromone is a nontoxic dietary supplement with some antitumor activity at high doses (450 – 3000 mg/day). HC inhibits hyaluronic acid (HA) synthesis. HA promotes tumor growth and metastasis. We recently showed that HA-receptors CD44 and RHAMM are potential predictors of mRCC. We examined the anti-tumor properties of HC, SF, and their combination in RCC models. METHODS Using proliferation, clonogenic and apoptosis assays, effects of HC (0–32 μg/ml), SF (0–3.2 μg/ml) and HC+SF were examined in RCC cells (Caki–1, 786–O, ACHN, A498) and endothelial cells (HMVEC–L, HUVEC). Boyden chamber was used for motility and invasion assays. Apoptosis indicators, HA receptors, EGFR and c-Met were evaluated by immunoblotting. Efficacy of HC, SF and HC+SF was evaluated in the SF-resistant Caki–1 xenograft model. RESULTS HC+SF synergistically inhibited proliferation (>95%), motility/invasion (65%) and capillary formation (76%) in RCC and/or endothelial cells, and induced apoptosis by 8-fold (P<0.001). HC+SF inhibited HA synthesis and HA addition reversed the cytotoxicity of HC+SF. HC+SF up-regulated pro-apoptotic indicators and downregulated Mcl-1, CD44, RHAMM, phospho-EGFR and phospho-cMet levels. In all assays, HC and SF alone were ineffective. Oral administration of HC (50–200mg/kg) plus SF (30mg/kg) eradicated Caki–1 tumor growth without toxicity. HC and SF alone were ineffective. CONCLUSION This is the first study that demonstrates combination of SF with HC a non–toxic dietary supplement is highly effective in controlling RCC.