Purpose: This first-in-human trial aimed to investigate the pharmacokinetics and pharmacodynamics characteristics and safety and tolerability of single ascending doses of subcutaneous polyethylene glycol-erythropoietin (PEG-EPO) in healthy subjects. Methods: In this phase I, randomized, double-blind, placebo-controlled, dose-escalating trial, subjects were sequentially enrolled into 7 cohorts with 12 subjects in each cohort and randomized in a 5:1 ratio to receive a single dose of 0.2, 0.4, 0.8, 1.6, 2.4, 3.6, or 4.8 mu g/kg PEG-EPO or matching placebo. Safety and tolerability including dose-limiting toxicities (DLTs) were assessed. Pharmacokinetics parameters, including C max , AUC 0-inf , T max , and t 1/2 , and pharmacodynamics parameters, including reticulocyte count and hemoglobin content, were evaluated. Findings: Eighty-four subjects (median age 30.4 years and 77.4% male) were enrolled. No subjects developed DLTs. Any grade treatment-related adverse events occurred in 66.7% of the subjects, but most (92.9%) were mild. No serious adverse events and no death occurred. Forty percent of the subjects receiving PEG-EPO had iron decreased, 27.1% reported ferritin decreased, 25.7% showed unsaturated iron binding capacity increased, and 17.1% had neutrophil count decreased. C max exhibited a dose-disproportionate rise from a geometric mean of 525 pg/mL with 0.2 mu g/kg PEG-EPO to 23196 pg/mL with 4.8 mu g/kg PEG-EPO. The mean t 1/2 ranged between 82.4 +/- 21.3 h with 0.4 mu g/kg PEG-EPO and 160.6 +/- 65.7 h with 1.6 mu g/kg PEG-EPO. AUC 0-inf displayed a largely dose-proportional rise from 226264.5 pg & lowast;h/mL with 0.2 mu g/kg PEG-EPO to 5206434.0 pg & lowast;h/mL with 4.8 mu g/kg PEG-EPO. The absolute reticulocyte count increased with escalating doses of PEG-EPO, with the mean maximal change from baseline between 3.2 +/- 1.5 & lowast;1010/L (Q1,Q3 1.8-3.6 & lowast;1010/L) with PEG-EPO 0.2 mu g/kg and 9.3 +/- 4.0 & lowast;1010/L (Q1,Q3 6.2-13.5 & lowast;1010/L) with 3.6 mu g/kg PEG-EPO. The mean maximal change from baseline in the mean hemoglobin content ranged between 5.9 +/- 4.4 g/L (Q1,Q3 3.5,7.0) with 0.2 mu g/kg PEG-EPO and 15.4 +/- 8.7 g/L (Q1,Q3 10.5,20.0) with 2.4 mu g/kg PEG-EPO. Implications: This trial demonstrated that PEG-EPO was safe and tolerable in healthy subjects. The subcutaneous route of administration allows outpatient treatment and the pharmacokinetics characteristics of PEG-EPO support less frequent dosing regimens and effective treatment for chronic kidney disease patients with anemia. Trial registration: clinicaltrials.gov identifier: NCT03657238.