PURPOSE: This study evaluated whether recombinant human erythropoietin (rhEpo) treatment combined with hypoxia provided an additive effect on hemoglobin mass (Hbmass) and V̇O2peak compared to altitude or rhEpo alone. METHODS: 39 participants underwent two interventions, each containing 4 weeks baseline (PRE 1-4), 4 weeks exposure at sea level or 2,320 m of altitude (INT 1-4), and 4 weeks follow-up (POST 1-4). Participants were randomly assigned to 20 IU·kg-1 rhEpo or placebo injections every second day for 3 weeks during the exposure period at sea level (SL-EPO n = 25, SL-PLA n = 9) or at altitude (ALT-EPO n = 12, ALT-PLA n = 27). RESULTS: Hbmass displayed a significant time×treatment effect (P <
0.001) when comparing ALT-EPO and ALT-PLA. Specifically, the increase in Hbmass was higher (P <
0.05 to P <
0.001) for ALT-EPO from INT 2 to POST 3 except for POST 2. Similarly, a significant time×treatment effect (P <
0.001) existed for changes in Hbmass when comparing ALT-EPO with SL-EPO, with the increase in Hbmass being higher (P <
0.01 to P <
0.001) for ALT-EPO from INT 2 to POST 4. A significant time×treatment effect was present when SL-PLA was compared with ALT-PLA (P <
0.05) and SL-EPO (P <
0.05). For V̇O2peak the time×treatment interaction was not significant when comparing ALT-EPO to ALT-PLA. However, when ALT-EPO was compared with SL-EPO, a significant time×treatment interaction existed (P <
0.001) due to a decrease in V̇O2peak during altitude. CONCLUSIONS: The combined treatment of micro-doses of rhEpo and altitude exposure results in an additive increase in Hbmass but does not significantly enhance V̇O2peak compared to each treatment alone.