Many intensive care units (ICUs) have transitioned from systemic heparin anticoagulation (SHA) to regional citrate anticoagulation (RCA) for continuous kidney replacement therapy (CKRT). We evaluated the clinical and health economic impacts of ICU transition to RCA. We surveyed all adult general ICUs in England and Wales to identify transition dates and conducted a micro-costing study in eight ICUs. We then conducted an interrupted time-series analysis of linked, routinely collected health records. In 69,001 patients who received CKRT (8585 RCA, 60,416 SHA) in 181 ICUs between 2009 and 2017, transition to RCA was not associated with a change in 90-day mortality (adjusted odds ratio 0.98, 95% CI 0.89–1.08) but was associated with step-increases in duration of kidney support (0.53 days, 95% CI 0.28–0.79), advanced cardiovascular support (0.23 days, 95% CI 0.09–0.38) and ICU length of stay (0.86 days, 95% CI 0.24–1.49). The estimated one-year incremental net monetary benefit per patient was £ − 2376 (95% CI £ − 3841–£ − 911), with an estimated likelihood of cost-effectiveness of <0.1%. Transition to RCA was associated with significant increases in healthcare resource use, without corresponding clinical benefit, and is highly unlikely to be cost-effective over a one-year time horizon. •No change in 90-day mortality with transition to regional citrate anticoagulation.•Regional citrate anticoagulation increased intensive care stay and organ support.•Regional citrate anticoagulation costs significantly more than systemic heparin.