Background: Exertional periodic breathing (EPB) or anemia is associated with an adverse prognosis in advanced heart failure (HF). The disturbed rheological properties of erythrocytes may contribute to circulatory disorders. This study investigated whether EPB with/without anemia influences rheological/hemodynamic functions in patients with HF. Methods: According to the WHO criteria for anemia, 168 HF patients were divided into six groups: non (N)-anemic with (n = 27)/without (n = 56) EPB, light (L)-anemic with (n = 17)/without (n = 21) EPB, and moderate/several (M/S)-anemic with (n = 21)/without (n = 26) EPB groups. These HF patients and 30 healthy counterparts performed an incremental exercise test using a bicycle ergometer. Rheological and hemodynamic characteristics were determined by slit-flow ektacytometer and bioreactance-based device/near infrared spectrometer, respectively. Results: In the HF patients with EPB, both L- and M/S-anemic groups exhibited 1) higher plasma myeloperoxidase/interleukin-6 concentrations, 2) more blood senescent/spherical erythrocyte counts, 3) larger aggregability and smaller deformability of erythrocytes under shear flows, 4) higher systemic vascular resistance, which was accompanied by smaller amounts of blood distributed to cerebral/muscular tissues during exercise, 5) less VO2peak and ventilatory efficiency, and 6) lower Short Form-36 physical/mental component scores and higher Minnesota Living with HF questionnaire score than N-anemic group. Additionally, plasma myeloperoxidase/interleukin-6 levels were directly related to erythrocyte aggregability and inversely related to erythrocyte deformability. However, there were no significant differences in pro-inflammatory factors, rheological/hemodynamic properties, and aerobic capacity between L- and N-anemic groups in the HF patients without EPB. Conclusion: EPB potentiates anemia-related rheological/hemodynamic dysfunctions by elevating pro-inflammatory status, reducing physical fitness in patients with HF. © 2012 Elsevier Ireland Ltd.