Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries. The main preventive/therapeutic tool of NAFLD is currently the improvement of lifestyle. The purpose of this study is to evaluate the impact of a combined nutraceutical approach on the clinical and laboratory features of NAFLD patients. We consecutively enrolled 80 NAFLD patients in a double-blind, placebo-controlled, randomized clinical trial. After a 4 weeks stabilization diet period, we randomized them to assume a combined multivitamin/multimineral/botanical nutraceutical (Metaclear TM) 2 tablets per day or an identical placebo for 3 months. Patients were rechecked after further 30 days. Liver parameters significantly improved in the combined nutraceutical treated subjects. In particular, in a generalized linear mixed model with Fatty Liver Index (FLI) as dependent variable a significant period by treatment effect was observed (F-value = 22.5, p<0.001). For the patients treated with the combined nutraceutical, FLI decreased with on average 11.9 units and 13.6 units at the end of treatment and the follow-up visit compared to baseline, respectively. The decrease in FLI from baseline to the end of treatment and to follow-up was on average 5.9 units higher (95%C 3.3-8.4, p<0.001) and 8.6 units higher (95%CI 6.0-11.1, p<0.001) for the combined nutraceutical treated group in comparison to the placebo group, respectively. The short-term treatment with the combined nutraceutical has been associated with a significant improvement of NAFLD biomarkers.