To determine the effects of roxadustat on calcification when treating renal anemia in end-stage kidney disease (ESKD) patients. A prospective cohort study enrolled participants with ESKD that either received roxadustat or no roxadustat treatment. The primary outcome was the change in the degree of hydroxyapatite (HAP) crystals deposition. The secondary outcome was calcification propensity, a measure of calcification, allowing an evaluation of the conversion process from primary to secondary calciprotein particles. A total of 205 patients were enrolled, and 187 (91.2%) completed follow-up for inclusion in the analysis and were divided into the roxadustat group (n = 92) and the control group (n = 95) based on whether or not they were taking roxadustat regularly over a 6-month period. After roxadustat administration for 6 months, patients exhibited increases in total red blood cell counts, hematocrit, hemoglobin, calcium, total ferritin binding, iFGF23, SPP24, and calcification propensity relative to pre-treatment levels. No significant differences were observed in patients who were not treated with roxadustat. The deposition degree of HAP crystals increased by 5% and 0.01% following treatment with roxadustat in the roxadustat group and control group, respectively. Linear regression analysis found that the use of roxadustat was an independent risk factor for calcification propensity and changes in the degree of HAP crystals deposition. Roxadustat treatment may increase iFGF23, SPP24, and calcification propensity in patients with ESKD when treating these patients for renal anemia. Therefore, the clinicians should aware of this risk when treating patients with PHIs.