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Background: Recombinant human erythropoietin (rHuEpo) abuse by athletes threatens the integrity of sport. Due to the overlap in physiological response to rHuEpo and altitude exposure, it remains difficult to differentiate changes in hematological variables caused by rHuEpo or altitude, and therefore, other molecular methods to enhance anti-doping should be explored. Objective: To identify the hematological and transcriptomic response to prolonged altitude exposure typical of practices used by elite athletes. Design: Longitudinal study. Setting: University of Cape Town and Altitude Training Centre in Ethiopia. Participants and Intervention: Fourteen well-trained athletes sojourned to an altitude training camp in Sululta, Ethiopia (;2400-2500mabove sea level) for 27 days. Blood samples were taken before arrival, 24 hours, and 9, 16, and 24 days after arrival at altitude in addition to 24 hours and 6, 13, and 27 days upon return to sea level. Main Outcome Measures: Blood samples were analyzed for hemoglobin concentration, hematocrit, and reticulocyte percentage. The transcriptomic response in whole blood and peripheral blood mononuclear cells (PBMC) were analyzed using gene expression microarrays. Results: A unique set of 29 and 10 genes were identified to be commonly expressed at every altitude time point in whole blood and PBMC, respectively. There were no genes identified upon return to sea level in whole blood, and only one gene within PBMC. Conclusions: The current study has identified a series of unique genes that can now be integrated with genes previously validated for rHuEpo abuse, thereby enabling the differentiation of rHuEpo from altitude exposure. [ABSTRACT FROM AUTHOR]