Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. Half of patients experience debilitating fatigue, which is currently untreatable. Previous studies have shown muscle bioenergetic abnormalities in PBC, including increased muscle acidosis with exercise linked to the antimitochondrial antibody (AMA) diagnostic of the disease, and reduced anaerobic threshold. In this study we addressed the hypothesis that fatigue in PBC is driven by muscle bioenergetic abnormality related to AMA, and that AMA reduction with B‐cell depletion therapy will improve fatigue. In our single‐center phase 2 randomized controlled trial, 57 participants aged 18 years or older with PBC and moderate to severe fatigue were randomized to receive two doses of either rituximab (1000 mg) or saline (placebo). The primary outcome measure was fatigue severity assessed using the PBC‐40 fatigue domain at 3 months. Secondary outcome measures included patient‐reported outcomes and immunological and bioenergetics disease parameters. Experimental outcomes included biochemical markers of disease severity. Improvement in fatigue score at 3 months was seen in both arms, with no significant difference (adjusted mean difference −0.9 [95% confidence interval −4.6 to 3.1]). Little difference was observed in other patient‐reported outcomes or physical activity. Significant anaerobic threshold improvement was seen in the rituximab group, only but this was not associated with fatigue improvement. No treatment‐emergent serious adverse events were seen. Conclusions: Rituximab was safe over the 12‐month study period but showed no evidence of effectiveness for the treatment of fatigue in PBC. Anaerobic threshold improvement was seen, potentially linking AMA with muscle bioenergetics dysfunction; however, this was not related to improvement in fatigue. Rituximab had some evidence of a beneficial effect on alkaline phosphatase levels in this largely ursodeoxycholic acid (UDCA)–responding, early‐disease stage cohort.