Abstract Background and Aims Iron preparations are commonly administered with erythropoiesis-stimulating agents or hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PH inhibitors) in hemodialysis patients to promote hematopoiesis and prevent iron deficiency. A recent study highlighted the causal relationship between thrombosis and upregulated serum transferrin levels due to iron deficiency. Additionally, rapid increase of hemoglobin (Hb) during HIF-PH inhibitor use is also considered a risk factor for the development of thromboembolism. Therefore, monitoring iron parameters and Hb is essential for managing anemia and thrombosis risk. We investigated the impact of practice patterns of iron supplementation on iron metabolism in patients receiving a HIF-PH inhibitor enarodustat. Changes in D-dimer levels, a thrombosis-related factor, were also assessed. Method We performed a post-hoc analysis using pooled data from two phase 3 clinical studies of enarodustat in Japanese maintenance hemodialysis patients, SYMPHONY HD and SYMPHONY HD-Long studies. We divided the subjects into three groups according to practice patterns of iron administration: subjects who did not receive iron at all during the enarodustat administration period (Non-Iron Group), subjects who received intravenous iron at least once (IV Iron Group), and subjects who continuously received oral iron-containing preparations including ferric citrate (Oral Iron Group). The time courses of transferrin saturation (TSAT), serum ferritin, and D-dimer levels were compared across these three groups using mixed effects models for repeated measures (MMRM) (with an unstructured covariance structure for the dependent variables). Results The Non-Iron Group, IV Iron Group, and Oral Iron Group consisted of 60, 69, and 73 cases, respectively. Figures show the time courses of TSAT, serum ferritin levels, and changes in D-dimer levels for each practice pattern. MMRM analysis revealed that TSAT levels in the Non-Iron Group and IV Iron Group during the enarodustat administration period were significantly lower than those in the Oral Iron Group (p < 0.01 and p < 0.01, respectively). Similar results were observed for serum ferritin levels (p < 0.01 and p < 0.01, respectively). Moreover, the rate of D-dimer increase in the Non-Iron Group was significantly higher than in the Oral Iron Group (p = 0.029). There was a trend toward a higher rate of D-dimer increase in IV Iron Groups compared to the Oral Iron Group (p = 0.11). Conclusion These findings suggest the superiority of continuous oral iron supplementation over intermittent IV iron supplementation or no iron supplementation during HIF-PH inhibitor administration in terms of preventing thrombosis through maintaining TSAT levels. The association between iron-related parameters and the occurrence of thrombosis needs to be analyzed.