End-stage renal disease (ESRD) is commonly associated with complaints of disturbed sleep and sleep disorders, frequently related to periodic limb movements in sleep (PLMS) or sleep apnea that may result in daytime sleepiness and other sequelae. Improvements in quality of life, including subjective sleep quality, have been reported in ESRD patients treated with recombinant human erythropoietin (rHuEPO). We investigated the objective effects of normalizing hematocrit on sleep disorders, sleep patterns, and daytime ability to remain awake in ESRD patients. Ten hemodialysis patients with sleep complaints while on rHuEPO therapy were studied by polysomnography while moderately anemic (mean hematocrit, 32.3%) and again when hematocrit was normalized (mean hematocrit, 42.3%) by increased rHuEPO dosing. Sleep patterns and associated parameters were monitored. Delivered dialysis dose and iron storage factors were monitored. Maintenance of Wakefulness Testing (MWT) was performed to assess daytime alertness/sleepiness. All 10 subjects experienced highly statistically significant reductions in the total number of arousing PLMS (P = 0.002). Nine of 10 subjects showed reductions in both the Arousing PLMS Index (P < 0.01) and the PLMS Index (P = 0.03) when hematocrit was normalized. Measures of sleep quality showed trends to improved quality of sleep. MWT demonstrated significant improvement in the length of time patients were able to remain awake (9.7 versus 17.1 minutes; P = 0.04). RHuEPO therapy with full correction of anemia reduces PLMS, arousals from sleep, and sleep fragmentation while allowing for more restorative sleep and improved daytime alertness. These findings may explain one mechanism for the improved quality-of-life parameters reported in ESRD patients treated with rHuEPO.