Elevation of hemoglobin concentration, a common adaptive response to high-altitude hypoxia, occurs among Oromo, but is dampened among Amhara highlanders of East Africa. We hypothesized that Amhara highlanders offset their smaller hemoglobin response with a vascular response. We tested this by comparing Amhara and Oromo highlanders at 3700 m and 4000 m to their lowland counterparts at 1200 m and 1700 m. To evaluate vascular responses, we assessed urinary levels of nitrate (NO₃^–) as a readout of production of the vasodilator nitric oxide and its downstream signal transducer cyclic guanosine monophosphate (cGMP), along with diastolic blood pressure as an indicator of vasomotor tone. To evaluate hematological responses, we measured hemoglobin and percent oxygen saturation of hemoglobin. Amhara highlanders, but not Oromo, had higher NO₃^– and cGMP compared to their lowland counterparts. NO₃^– directly correlated with cGMP (Amhara R²=0.25, P<0.0001; Oromo R²=0.30, P<0.0001). Consistent with higher levels of NO₃^– and cGMP, diastolic blood pressure was lower in Amhara highlanders. Both highland samples had apparent left shift in oxyhemoglobin saturation characteristics, and maintained total oxyhemoglobin content similar to their lowland counterparts. However, deoxyhemoglobin levels were significantly higher, much more so among Oromo than Amhara. In conclusion, the Amhara balance minimally elevated hemoglobin with vasodilatory response to environmental hypoxia, whereas Oromo rely mainly on elevated hemoglobin response. These results point to different combinations of adaptive responses in genetically similar East African highlanders.