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Uncertainty exists regarding the treatment of patients with nonalcoholic fatty liver disease (NAFLD) who are unable to lose weight and/or change lifestyle. The present study assesses the effectiveness and safety of pharmacological and dietary supplement interventions for NAFLD.MEDLINE, EMBASE, and the Cochrane Library were searched for randomized controlled trials (RCTs) both in adults and in children.Fifteen (2 pediatric patients and 13 adults) RCTs met the inclusion criteria. A significant effect on normalization of alanine transaminase was found in patients treated with metformin compared with vitamin E, and in those treated with high-dose (3 g) carnitine vs diet. In contrast, there was no difference in patients treated with pioglitazone combined with vitamin E versus vitamin E alone, ursodeoxycholic acid (UDCA) combined with vitamin E or alone versus placebo, or UDCA versus combination of vitamin E and vitamin C, and in patients treated with vitamin E, probucol, N-acetylcysteine, low doses of carnitine, or Yo Jyo Shi Ko compared with placebo. Aspartate aminotransferase normalization was significantly higher in those treated with UDCA combined with vitamin E versus UDCA alone or placebo, and in those treated with metformin. Small number of subjects, high drop-out rates, and numerous interventions in 1 study limit the value of many studies. Only 7 RCTs analyzed biopsy specimens, but most of them have significant methodological limitations. Pioglitazone had reduced liver necrosis and inflammation in 1 large study.Limited data do not allow one to draw firm conclusions on the efficacy of various treatments for NAFLD.