Background. Secondary hyperparathyroidism (SHPT) is a major risk factor for cardiovascular events and all-cause mortality in hemodialysis (HD) patients. The purpose of our study was to evaluate the effects and tolerability of etelcalcetide in HD patients with SHPT. Methods. An observational study was conducted on 16 hemodialysis patients with SHPT treated with etelcalcetide. All patients were followed up for a duration of 6 months. The primary endpoints were the reduction in mean PTH ≥ 30% and ≥40% from baseline after 6 months of etelcalcetide. All patients were divided into two groups (group A versus group B) based on baseline serum PTH level prior to etelcalcetide: above and below the median serum PTH (1300 pg/mL), respectively. Results. After 6 months, a significant decrease in PTH levels was achieved by all patients receiving etelcalcetide (p
= 0.015). Both primary endpoint of reduction in PTH ≥ 40% at 6 months (p
= 0.01), and the secondary endpoint of reduction in median PTH values (p
= 0.0001) and median percentage reduction in PTH values (p
= 0.009) were significantly achieved in group A. In contrast, a greater decline of calcium (p
= 0.028) and phosphorus was reached in group B than group A. Dialysis vintage ≥ 36 months, arteriovenous fistula (AVF)-based hemodialysis, post-diluition hemodiafiltration (HDF) method, and baseline values of PTH < 1300 pg/mL can positively influence the achievement of the endpoints. Furthermore, the baseline PTH < 1300 pg/mL, among these variables, was the only one showing statistically significant relevance (OR 2.28, 95% CI 1.32–3.96, p
= 0.015). The history of cinacalcet use negatively correlated with the possibility to reach therapeutic targets with etelcalcetide (OR 0.47, 95% CI 0.26–0.85, p
= 0.031). Treatment with etelcalcetide was well tolerated and no adverse effects were observed. Conclusions. In our study, patients with low baseline PTH levels showed a better response to etelcalcetide than patients with higher PTH levels. Consequently, the possibility to reach desirable therapeutic targets could depend on SHPT severity at the time of initiation of therapy.