Steatosis is a prominent feature of non-alcoholic fatty liver disease and potential promoter of inflammation. Injury leading to cirrhosis is partly mediated by dysregulation of matrix protein turnover. Matrix metalloproteinase (MMP) inhibitors protect mice from lethal TNF- induced liver injury. We hypothesized that Marimastat^TM, a broad-spectrum MMP and TNF- converting enzyme (TACE) inhibitor, might modulate injury through interruption of inflammatory pathways. Triglyceride and phospholipid levels (liver, serum) and fatty acid profiles were used to assess essential fatty acid status and de novo lipogenesis as mechanisms for steatosis. Mice receiving a fat-free, high carbohydrate diet (HCD) for 19 days developed fatty liver infiltration, demonstrated by histology, MR-spectroscopy, and elevated liver function tests. Animals receiving HCD plus Marimastat^TM (HCD+MAR) were comparable to control. Increased levels of Peroxisome Proliferator Activated Receptor Alpha (PPAR-), higher levels of serum IL-6, and decreased levels of serum Tumor Necrosis Factor Alpha (TNF-) receptor II were seen in the HCD+MAR group in comparison to HCD-only. There was increased phosphorylation, and activation, of PPAR- in the HCD+MAR group. PPAR- is a transcription factor involved in -oxidation of fatty acids and IL-6 is a hepatoprotective cytokine. Liver triglyceride levels were higher and serum triglyceride and phospholipid levels lower with HCD-only, but improved with Marimastat^TM treatment. HCD-only and HCD+MAR groups were essential fatty acid deficient and had elevated rates of de novo lipogenesis. We therefore conclude that Marimastat^TM reduces liver triglyceride accumulation by increasing fat oxidation and/or liver clearance of triglycerides, possibly related to increased expression/activation of PPAR- or IL-6, respectively.