The beneficial effects of mineralocorticoid receptor blockade by spironolactone have been shown in animal models of non-alcoholic fatty liver disease (NAFLD). The aim of the present 52-week randomized controlled trial was to compare the effects of low-dose spironolactone and vitamin E combination with those of vitamin E monotherapy on insulin resistance, non-invasive indices of hepatic steatosis and fibrosis, liver function tests, circulating adipokines and hormones in patients with histologically confirmed NAFLD. Homeostasis model of assessment of insulin resistance (HOMA-IR) and non-invasive indices of steatosis and fibrosis were calculated. Analysis was intention-to-treat. NAFLD liver fat score, an index of steatosis, decreased significantly in the combination treatment group (P = .028), but not in the vitamin E group, and the difference for group*time interaction was significant (P = .047). Alanine aminotransferase-to-platelet ratio index, an index of fibrosis, did not change. Insulin levels and HOMA-IR decreased significantly only within the combination group (P = .011 and P = .011, respectively). In conclusion, the combined low-dose spironolactone plus vitamin E regimen significantly decreased NAFLD liver fat score. Larger-scale trials are needed to clarify the effect of low-dose spironolactone on hepatic histology.