Roxadustat, a novel hypoxia-inducible factor prolyl hydroxylase inhibitor, has emerged as an alternative treatment for renal anemia, particularly in patients with erythropoiesis-stimulating agent(ESA) hyporesponsiveness. However, the complex etiology of anemia in chronic kidney disease(CKD) patients presents significant challenges to its application. Herein we report a 54-year-old woman with stage 5 CKD undergoing peritoneal dialysis, who experineced severe anemia unresponsive to high-dose erythropoietin(EPO)(10,000 U twice weekly) and blood transfusions. The treatment was switched to Roxadustat at 120mg three times per week, resulting in a rapid hemoglobin increase to 151g/L within several months. However, she subsequently developed jaundice, and genetic testing revealed heterozygous β-thalassemia. The jaundice was attributed to hemolysis and intrahepatic microvascular thrombosis, possibly exacerbated by Roxadustat. This case highligts the diagnostic and therapeutic challenges with managing anemia in CKD patients with ESA hyporesponsiveness, where multiple factors, including chronic inflammation, iron metabolism disorders and hemeglobinopathies like β-thalassemia, may coexist. While roxadustat effecively corrected anemia in this patients, it also underscored potential risks, including exacerbation of hemolysis and thrombotic complications. In summary, the case highlights the multifactorial nature of ESA hyporesponsiveness and suggests that underlying conditions may influence the safety profile of roxadustat. It emphasizes the necessity for comprehensive diagnostic evaluation, close monitoring and individualized treatment strategies for managing anemia in CKD patients with complex underlying etiologies.