We studied sea-level residents during 13 days of altitude acclimatization to determine 1) altitude acclimatization effects on erythrocyte volume and plasma volume, 2) if exogenous erythrocyte volume expansion alters subsequent erythrocyte volume and plasma volume adaptations, 3) if an increased blood oxygen content alters erythropoietin responses during altitude acclimatization, and 4) mechanisms responsible for plasma loss at altitude. Sixteen healthy men had a series of hematologic measurements made at sea level, on the first and ninth days of altitude (4,300 m) residence, and after returning to sea level. Twenty-four hours before the ascent to altitude, one group received a 700-ml infusion of autologous erythrocytes (42% hematocrit), whereas the other group received only a saline infusion. Erythrocyte infusion increased erythrocyte volume by approximately 10%, whereas saline infusion had no effect; in addition, initially at altitude, blood oxygen content was 8% higher in erythrocyte-infused than in saline-infused subjects. The new findings regarding altitude acclimatization are summarized as follows: 1) erythrocyte volume does not change during the first 13 days and is not affected by prior exogenous expansion, 2) a modest increase in blood oxygen content does not modify erythropoietin responses, 3) plasma losses are related to vascular protein losses, and 4) exogenous erythrocyte volume expansion coincides with transient increases in plasma loss, vascular protein loss, and mean arterial pressure elevation. These findings better define human blood volume responses during altitude acclimatization.