It is classically thought that increases in hemoglobin mass (Hbmass) take several weeks to develop upon ascent to high altitude and are lost gradually following descent. However, the early time course of these erythropoietic adaptations has not been thoroughly investigated and data are lacking at elevations greater than 5000 m, where the hypoxic stimulus is dramatically increased. As part of the AltitudeOmics project, we examined Hbmass in healthy men and women at sea level (SL) and 5260 m following 1, 7, and 16 days of high altitude exposure (ALT1/ALT7/ALT16). Subjects were also studied upon return to 5260 m following descent to 1525 m for either 7 or 21 days. Compared to SL, absolute Hbmass was not different at ALT1 but increased by 3.7 ± 5.8% (mean ± SD; n = 20; p<0.01) at ALT7 and 7.6 ± 6.6% (n = 21; p<0.001) at ALT16. Following descent to 1525 m, Hbmass was reduced compared to ALT16 (-6.0 ± 3.7%; n = 20; p = 0.001) and not different compared to SL, with no difference in the loss in Hbmass between groups that descended for 7 (-6.3 ± 3.0%; n = 13) versus 21 days (-5.7 ± 5.0; n = 7). The loss in Hbmass following 7 days at 1525 m was correlated with an increase in serum ferritin (r = -0.64; n = 13; p<0.05), suggesting increased red blood cell destruction. Our novel findings demonstrate that Hbmass increases within 7 days of ascent to 5260 m but that the altitude-induced Hbmass adaptation is lost within 7 days of descent to 1525 m. The rapid time course of these adaptations contrasts with the classical dogma, suggesting the need to further examine mechanisms responsible for Hbmass adaptations in response to severe hypoxia.