BACKGROUND AND AIMS: Pathophysiological features of hypertrophic cardiomyopathy include left ventricular hypertrophy, myocardial fibrosis, and myocardial energy deficiency. Depletion of cardiomyocyte copper I ions leads to impaired mitochondrial function, a state associated with left ventricular hypertrophy. Unbound or loosely bound copper II ions activate profibrotic pathways. Trientine dihydrochloride improves intracellular copper I ion trafficking and availability, and chelates copper II ions. In preclinical studies, trientine improved myocardial mitochondrial function and reduced left ventricular hypertrophy and fibrosis. The efficacy and safety of trientine in persons with hypertrophic cardiomyopathy are unknown. METHODS: In this multicentre, placebo-controlled phase 2 trial, adults with hypertrophic cardiomyopathy, a left ventricular wall thickness of 15 mm or greater, and who were in New York Heart Association class I to III were randomly assigned to receive trientine 400 mg twice daily or placebo for 52 weeks. Patients with any left ventricular outflow tract (LVOT) gradient were eligible. The primary endpoint was the change in left ventricular mass indexed to body surface area measured using cardiovascular magnetic resonance. RESULTS: A total of 154 patients underwent randomization. The mean age was 53.4 years, median maximum left ventricular wall thickness was 20.0 mm, median maximum LVOT gradient was 6.0 mmHg, 18.6% of patients had a resting LVOT gradient ≥30 mmHg, and 61.7% were in New York Heart Association class I. At 52 weeks, the mean change in the left ventricular mass indexed to body surface area was -4.4 ± 7.7 g/m2 in the trientine group and -1.5 ± 6.1 g/m2 in the placebo group (between-group difference -3.2 g/m2; 95% confidence interval -5.6 to -0.8; P = .009). The efficacy of trientine increased at higher levels of baseline left ventricular mass (baseline left ventricular mass indexed to body surface area by treatment allocation interaction P = .015). The effect of trientine was mediated via a reduction in myocardial cellular mass (average causal mediated effect -3.9 g/m2; 95% confidence interval -6.8 to -0.9). The incidence of adverse events was similar in the two groups. CONCLUSIONS: Among patients with hypertrophic cardiomyopathy, treatment with trientine resulted in a significantly greater reduction in left ventricular mass indexed to body surface area than placebo. (Funded by NIHR; TEMPEST ClinicalTrials.gov number, NCT04706429).