NOS-activation in erythrocytes (eryNOS) is impaired in patients suffering from type 2 diabetes. We investigated the effect of physical exercise on eryNOS activation and whether 6 week hypoxia interval training may alter this process. Male patients with diabetes mellitus type 2 (NIDDM, n = 12; age, 61.3 ± 8.4 years; BMI, 29.8 ± 3.7 kg/m(2)) underwent physical exercise training before and after 6 week hypoxia interval training. Training was conducted 4 times per week for 90 min at 15.4-12.7 Vol% of inspired oxygen. Vital parameters were recorded. Before hypoxia intervention, eryNOS phosphorylation at serine(1177) decreased significantly during exercise (basal 17.4 ± 12.0 compared with exercise 8.4 ± 9.2 arbitrary grey values (arGV); P < 0.05). After 6 weeks of hypoxia intervention, eryNOS-pSer(1177) (2.2 ± 2.5 arGV) was significantly lower at baseline. Ergometry showed an increase (7.6 ± 3.0 arGV; P < 0.05) followed by a decrease to almost baseline levels after 30 min (3.8 ± 1.5 arGV). Maximal exercise capacity and O(2)-uptake ([Formula: see text] max) increased significantly. The effects were independent from exercise-induced elevation of blood pressure. Exercise-dependent eryNOS phosphorylation at serine(1177) was increased similar to that described for the endothelium in diabetic patients. EryNOS dysregulation was partially restored after intermittent hypoxia training.