Suboptimal response to recombinant human erythropoietin (rHuEPO) is common in a substantial percentage of patients with chronic kidney disease. Consequently, a higher dose of rHuEPO is needed to attain target haematocrit (Hct) in such patients. Variables that affect rHuEPO dose requirements can be broadly divided into modifiable and immutable characteristics. To date, most of the scientific studies on rHuEPO hyporesponsiveness have focused on modifiable variables that affect rHuEPO response, such as iron status and dialysis adequacy, while exploration of immutable variables has received less attention. This review addresses the key immutable variables that have been suggested as potential determinants of rHuEPO dose requirement. Several investigators, on the basis of analysis of large patient databases, have suggested that diabetic individuals, women, and Black patients on haemodialysis (HD) require a higher dose of rHuEPO than their respective counterparts to attain target Hct. It is unclear whether the observed differences in achieved Hct are due to inherent biological differences in responsiveness to rHuEPO or failure of the investigators to account for modifiable variables that affect rHuEPO dose requirement. Protocol studies with specific a priori hypotheses have failed to confirm some of the findings from these large database analyses. Factors, such as nutritional status, pregnancy, duration of end-stage renal disease, and type of HD vascular access can all potentially modulate response to rHuEPO and should also be considered.