A reduction in O2 affinity of hemoglobin should increase tissue oxygenation or maintain tissue oxygenation and at the same time spare cardiac work. Large, sustained reductions in O2 affinity of hemoglobin are induced best by primary (non-Bohr effect) stimulation of red blood cell 2,3-diphosphoglycerate (DPG) caused by a dual, cumulative effect on O2 affinity for hemoglobin, direct, from DPG itself, and indirect, from DPG-induced red blood cell acidosis. In an attempt to induce significant, sustained reductions in O2 affinity of hemoglobin by primary DPG stimulation, six normal humans were given a diphosphonate (etidronate disodium [Didronel] 20 mg/kg/day p.o.) followed by infusion of 10% fructose (0.5 L/hr for 3 hours) with added phosphate (0.28 mmol/kg/hr) and, subsequently, fructose-phosphate by itself. Participants underwent exercise testing (bicycle ergometer) and cardiopulmonary parameters were measured before and after administration of Didronel plus fructose-phosphate infusion, as well as before and after fructose-phosphate infusion alone. The sum of DPG and adenosine triphosphate as well as the P50 increased significantly after infusion of fructose-phosphate with and without prior administration of Didronel. DPG-ATP correlated closely with P50. When P50 was elevated, the cardiac index at high work load was lower than when P50 was normal (with comparable O2 consumption); changes in P50 correlated inversely with changes in cardiac index. Thus, with reduced O2 affinity of hemoglobin, participants could perform at comparable work loads and utilize the same amount of O2 with less cardiac work. Future studies should include adapting these findings to states of O2 deficit.