Objective <p>This study aimed to investigate the etiology, clinical manifestations, management strategies, and clinical outcome of hemodialysis-related allergic reactions.</p> Methods <p>A retrospective cohort study was conducted to analyze clinical data from patients who experienced hemodialysis-related allergic reactions at the Affiliated Hospital of Jiangnan University between January 2020 and December 2025. Patients undergoing maintenance hemodialysis—with no prior history of these allergic reactions—served as the control group. Their clinical characteristics and reaction profiles were systematically analyzed.</p> Results <p>A total of 40 cases of hemodialysis-related allergic reactions were identified as the study group. Isolated pruritus and skin rash were observed in 25 patients (62.5%); hemodialysis-related leukopenia and thrombocytopenia, in 4 cases (10.0%); and severe anaphylactic reactions, in five cases (12.5%); Five cases exhibited atypical hemodialysis-related allergic reactions (12.5%), including hypotension within 10&#xa0;min of hemodialysis initiation, malaise, nausea, and vomiting. The predominant etiological factors identified were hypersensitivity to the hemodialyzer membrane (<i>n</i> = 11, 27.5%), AVF needles kits and hemodialysis extracorporeal circuit tubing (Ethylene Oxide Residue) (<i>n</i> = 27, 67.5%), and Nafamostat Mesylate (<i>n</i> = 2, 5%). Thorough saline pre-rinsing of the extracorporeal circuit remained the primary preventive strategy against EO-induced hypersensitivity. Switching to irradiated-sterilized acetate-membrane or wet-membrane dialyzers effectively prevented dialyzer hypersensitivity reaction. Glucocorticoid administration was effective in mitigating severe anaphylactic reactions. Patients in the study group exhibited significantly higher plasma eosinophil counts and C-reactive protein concentrations, and significantly lower hemoglobin levels, and serum albumin concentrations compared with the control group.</p> Conclusion <p>Hemodialysis-related allergic reactions are primarily attributable to hypersensitivity responses to dialyzer membranes, residual ethylene oxide in extracorporeal circuit components, and occasionally Nafamostat Mesylate administered during the procedure. Glucocorticoid administration was effective in attenuating severe anaphylactic reactions. Allergic reactions that repeatedly occur during hemodialysis may be associated with an underlying chronic micro-inflammatory state.</p>