Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are novel, orally administered agents for anemia management in chronic kidney disease (CKD). We evaluated the cardiac and kidney-related adverse effects of HIF-PHIs among patients with CKD.Systematic review and meta-analysis of randomized controlled trials (RCTs).Patients with anemia and CKD not receiving maintenance dialysis.RCTs comparing HIF-PHIs to placebo or an erythropoiesis-stimulating agent (ESA) with primary outcomes of cardiac and kidney-related adverse events.Two independent reviewers evaluated RCTs for eligibility and extracted relevant data.Dichotomous variables were pooled using the Mantel-Haenszel method and presented as risk ratios (RRs) with 95% confidence intervals (CI). Subgroup analyses evaluated different intervention times and HIF-PHIs, as well as phase 2 vs. phase 3 trials. The certainty of findings was rated according to GRADE criteria.Twenty-three studies with 15,144 participants were included. No significant difference in the risk of cardiac disorders was observed between the HIF-PHIs group and the placebo (RR=1.02; 95% CI, [0.89 to 1.16]; moderate certainty) or ESA groups (RR=1.06; 95% CI, [0.98 to 1.14]; low certainty). No significant difference in the risk of kidney-related adverse events was observed between the HIF-PHIs group and the placebo (RR=1.09; 95% CI, [0.98 to 1.20]; moderate certainty) or ESA groups (RR=1.00; 95% CI, [0.94 to 1.06]; low certainty).The occurrence of hypertension and hyperkalemia was higher in the HIF-PHIs group than in the placebo group (RR=1.35; 95% CI, [1.14 to 1.60]; high certainty and RR=1.25; 95% CI, [1.03 to 1.51]; high certainty, respectively). The occurrence of hypertension was lower in the HIF-PHIs group than in the ESA group (RR=0.89; 95% CI, [0.81 to 0.98]; moderate certainty). .The reporting criteria of cardiac and kidney-related events and dosage of HIF-PHIs were inconsistent across trials.The occurrence of cardiac or kidney-related adverse events in the HIF-PHI groups were not different compared with placebo or ESA groups.Registered at PROSPERO with record number CRD42021228243.Copyright © 2022. Published by Elsevier Inc.