Erythropoietin is used routinely in hemodialysis patients to increase hemoglobin levels in patients with ESRD and anemia. Considering the importance of anemia in hemodialysis patients and its complications, in this study, the effect of erythropoietin administration on blood parameters by comparing the methods of subcutaneous and intravenous administrations was investigated. The research was done as a retrospective descriptive-analytic study. The subjects were 300 hemodialysis patients receiving erythropoietin in two groups (intravenous and subcutaneous) from hospitals affiliated to Kurdistan and Kermanshah University of Medical Sciences. Data were extracted from the patients' records and entered into a researcher-made checklist during 6 months and analyzed using SPSS version 20 and descriptive and inferential statistics. The results showed that there was a significant difference between the mean rank of hematocrit in subcutaneous and intravenous injections (P-value = 0.002) and it was higher in the subcutaneous injection group. Also, independent t-test showed that there was a significant difference between the mean of hemoglobin concentration among subcutaneous and intravenous injections (P-value = 0.001) and it was higher in the subcutaneous injection group. However, there was no significant difference between the mean of ferritin in both groups (P-value = 0.084). According to the results, the injection of erythropoietin in the subcutaneous method was more effective than intravenous. It is recommended to use this approach to improve blood indices in hemodialysis patients.