Summary Background Oltipraz is a synthetic dithiolethione with an antisteatotic effect by inhibiting the activity of liver X receptor alpha (LXR‐α). Recent studies demonstrated the disruptive role of oltipraz on LXR‐α‐dependent lipogenesis in hepatocytes and a high‐fat diet mouse model. Aim To evaluate the efficacy and safety of oltipraz for reducing liver fat in subjects with non‐alcoholic fatty liver disease (NAFLD). Methods We performed a multicentre, double‐blind, placebo‐controlled, phase II study. Subjects with a liver fat >20% and hypertransaminasemia were randomised to the three groups: placebo (n = 22), 30 mg of oltipraz (n = 22) or 60 mg of oltipraz (n = 24) twice daily for 24 weeks. Changes in the liver fat from baseline to 24 weeks quantified using magnetic resonance spectroscopy were the primary outcome. Results Compared with the placebo group (−3.2 ± 11.1%), absolute changes in the liver fat content increased in a dose‐dependent manner: −7.7 ± 7.0% and −13.9 ± 10.7% for the low‐dose and high‐dose groups (P = 0.13 and P < 0.01). Per cent reduction in the liver fat content was also significantly greater in the high‐dose group than in the placebo group (−34.6 ± 29.4% vs. −0.6 ± 62.9%, P = 0.046). Body mass indices (−1.0 ± 0.9% vs. −0.5 ± 1.4%, P = 0.04) significantly decreased in the high‐dose group compared to the placebo group. However, absolute changes in insulin resistance, liver enzymes, lipids and cytokines were not significantly different among groups. The incidence of adverse events was comparable among groups. Conclusions Twenty‐four‐week oltipraz treatment significantly reduced the liver fat content in patients with NAFLD. Clinicaltrials.gov (NCT01373554). Linked ContentThis article is linked to Ajmera and Loomba, Wang and Lin, and Kim and Kim papers. To view this article visit https://doi.org/10.1111/apt.14081, https://doi.org/10.1111/apt.14122 and https://doi.org/10.1111/apt.14146.