BACKGROUND: Non-alcoholic steatohepatitis (NASH) has become one of the leading causes of liver disease in the western world. In obese patients weight reduction is recommended. Up to now there are no specific guidelines for weight loss in order to reduce hepatic fat content. AIM: To investigate the effects of a 24-wk guided lifestyle intervention program compared to a meal replacement regimen based on soy protein. METHODS: Twenty-six subjects with NASH participated in a randomized single-center study. They were randomly assigned to either meal replacement group (MR-G) with soy-yogurt-honey preparation or to guided lifestyle change group (LC-G) with endurance activity and nutrition counselling. Serum alanine transaminase (ALT), aspartate transaminase (AST), lipid parameters, and adipokines were measured. Liver fat content and lipid composition were determined by magnetic resonance imaging and magnetic resonance spectroscopy. Body fat mass and lean body mass were assessed using Bod Pod® device. Pre- and post-intervention monitoring of parameters was performed. Statistical analyses were conducted with SPSS software, results were expressed as median (interquartile range). RESULTS: Twenty-two subjects (MR-G, n = 11 and LC-G, n = 11) completed the study (9 women, 13 men; age 52.1 (15.0) years, body mass index (BMI) 32.3 (3.3) kg/m²). In both groups a significant weight loss was achieved (MR-G: -6.4 (3.6) kg, P < 0.01; LC-G: -9.1 (10.4) kg, P < 0.01). BMI dropped in both groups (MR-G: -2.3 (1.5) kg/m2, P = 0.003; LC-G: -3.0 (3.4) kg/m2, P = 0.006). Internal fat and hepatic lipid content were markedly reduced in both groups in comparable amount. There was a strong correlation between reduction in liver fat and decrease in ALT. Likewise, both groups showed an improvement in glycemic control and lipid profile. Changes in adipokines, particularly in adiponectin and leptin were closely related to intrahepatic lipid changes. CONCLUSION: Comprehensive lifestyle intervention and meal replacement regimen have comparable effects on body and liver fat, as well as decrease in markers of hepatic inflammation among NASH patients.