Inflammation is implicated in the pathogenesis of erythropoietin (EPO) resistance in patients with end-stage renal disease. Interleukin (IL)-6 and tumor necrosis factor (TNF)-α are suggested to suppress erythropoiesis in uremia. Insulin like growth factor (IGF)-1 has been proposed to stimulate erythropoiesis. Nocturnal hemodialysis (NHD) has been demonstrated to improve anemia management with enhanced EPO responsiveness without altering survival of red blood cells. We tested the hypothesis that augmentation of uremia clearance by NHD results in a reduction of proinflammatory cytokine levels, thereby enhancing EPO responsiveness. Using a cross-sectional study design, 14 prevalent patients on NHD and 14 patients on conventional hemodialysis (CHD) matched for age and comorbidities and controlled for hemoglobin concentrations and iron status were studied. Outcome variables included EPO requirement and plasma levels of EPO, parathyroid hormone, C reactive protein, IL-6, TNF-α, and IGF-1. The primary outcome was to determine the between group differences in (1) cytokine profile and (2) EPO requirement. The secondary outcome was to examine the potential correlation between cytokine levels and EPO requirement. There were no significant differences in patient characteristics, comorbidities, hemoglobin, iron indices, and parathyroid hormone levels between the two cohorts. EPO requirement was significantly lower in the NHD cohort [90.5 ± 22.1 U/kg/week (NHD) vs. 167.2 ± 25.4 U/kg/week (CHD), p = 0.04]. Plasma IL-6 levels were lower in the NHD cohort [3.9 ± 0.7 pg/ml (NHD) vs. 6.5 ± 0.8 pg/ml (CHD), p = 0.04]. C reactive protein tended to decrease [4.59 ± 1.34 (NHD) vs. 8.43 ± 1.83 mg/L (CHD), p = 0.14]. TNF-α, and IGF-1 levels did not differ between the two groups. Direct associations were found between EPO requirement and C reactive protein levels (R = 0.62, p = 0.001), and IL-6 levels (R = 0.57, p = 0.002). Augmentation of uremic clearance by NHD improves EPO responsiveness in end-stage renal disease. A possible mechanism for this improvement is through better control of inflammation, as manifested by lowering of plasma IL-6 levels. Further studies are required to clarify the mechanisms by which NHD decreases inflammation.