Rationale: Left ventricular hypertrophy (LVH) is highly prevalent in patients with chronic kidney disease and increases their risk of cardiac events and mortality. Fibroblast growth factor 23 (FGF23) and parathyroid hormone (PTH) levels, which are associated with the development of LVH, rise progressively with declining renal function. Objective: To determine whether FGF23 suppression by calcimimetic therapy may reduce LVH progression in comparison to FGF23 elevation under vitamin D analogs at equal PTH suppression under either therapy as well as tight volume control. Methods and Results: We conducted a single-blinded trial with 1:1 block randomization to investigate the effect of the intravenous treatment with etelcalcetide (ETL) versus alfacalcidol (ALFA) on LVH progression in 62 maintenance hemodialysis patients with secondary hyperparathyroidism and LVH. In the intention-to-treat analysis of 59 patients, the mean difference in the change of left ventricular mass index (LVMI) determined by cardiac magnetic resonance imaging from baseline to 12 months of treatment was -6.9 g/m² (95% confidence interval [CI] -12.6 to -1.2, p=0.022) in the ETL compared to the ALFA group. The effect estimate was -8.2 g/m² (95% CI -14 to -2.4) in the per-protocol analysis on 52 patients. The trajectories of PTH, phosphate and Klotho were similar in both groups throughout follow-up. FGF23 levels, which showed a strong positive association with LVMI, were decreasing under ETL and increasing under ALFA at similar PTH suppression. Mild hypocalcemia was the most common adverse event under ETL. Blood pressure and the distribution of antihypertensive medications were similar between groups. Conclusions: In this trial we were able to show that FGF23 suppression by ETL inhibited the progression of LVH compared to ALFA in hemodialysis patients. A successful prevention of increasing hypertrophy may reduce the risk of sudden cardiac death in this population.