Background: In a 72-week, randomised controlled trial of obeticholic acid (OCA) in non-alcoholic steatohepatitis (NASH), OCA was superior to placebo in improving serum ALT levels and liver histology. OCA therapy also reduced weight. Aims: Because weight loss by itself can improve histology, to perform a post hoc analysis of the effects of weight loss and OCA treatment in improving clinical and metabolic features of NASH. Methods: The analysis was limited to the 200 patients with baseline and end-of-treatment liver biopsies. Weight loss was defined as a relative decline from baseline of 2% or more at treatment end. Results: Weight loss occurred in 44% (45/102) of OCA and 32% (31/98) of placebo-treated patients (P = 0.08). The NAFLD Activity score (NAS) improved more in those with than without weight loss in both the OCA- (−2.4 vs −1.2, P<0.001) and placebo-treated patients (−1.2 vs −0.5, P = 0.03). ALT levels also improved in those with vs without weight loss in OCA- (−43 vs −34 U/L, P = 0.12) and placebo-treated patients (−29 vs −10 U/L, P = 0.02). However, among those who lost weight, OCA was associated with opposite effects from placebo on changes in alkaline phosphatase (+21 vs −12 U/L, P<0.001), total (+13 vs −14 mg/dL, P = 0.02) and LDL cholesterol (+18 vs −12 mg/dL, P = 0.01), and HbA1c (+0.1 vs −0.4%, P = 0.01). Conclusions: OCA leads to weight loss in up to 44% of patients with NASH, and OCA therapy and weight loss have additive benefits on serum aminotransferases and histology. However, favourable effects of weight loss on alkaline phosphatase, lipids and blood glucose seen in placebo-treated patients were absent or reversed on OCA treatment. These findings stress the importance of assessing concomitant metabolic effects of new therapies of NASH. Clinical trial number: NCT01265498.