Moderate-altitude living (2,500 m), combined with low-altitude training (1,250 m) (i.e., live high-train low), results in a significantly greater improvement in maximal O2 uptake (V(02)max) and performance over equivalent sea-level training. Although the mean improvement in group response with this "high-low" training model is clear, the individual response displays a wide variability. To determine the factors that contribute to this variability, 39 collegiate runners (27 men, 12 women) were retrospectively divided into responders (n = 17) and nonresponders (n = 15) to altitude training on the basis of the change in sea-level 5,000-m run time determined before and after 28 days of living at moderate altitude and training at either low or moderate altitude. In addition, 22 elite runners were examined prospectively to confirm the significance of these factors in a separate population. In the retrospective analysis, responders displayed a significantly larger increase in erythropoietin (Epo) concentration after 30 h at altitude compared with nonresponders. After 14 days at altitude, Epo was still elevated in responders but was not significantly different from sea-level values in nonresponders. The Epo response led to a significant increase in total red cell volume and V(O2) max in responders; in contrast, nonresponders did not show a difference in total red cell volume or V(O2)max after altitude training. Nonresponders demonstrated a significant slowing of interval-training velocity at altitude and thus achieved a smaller O2 consumption during those intervals, compared with responders. The acute increases in Epo and V(O2)max were significantly higher in the prospective cohort of responders, compared with nonresponders, to altitude training. In conclusion, after a 28-day altitude training camp, a significant improvement in 5,000-m run performance is, in part, dependent on 1) living at a high enough altitude to achieve a large acute increase in Epo, sufficient to increase the total red cell volume and V(O2)max, and 2) training at a low enough altitude to maintain interval training velocity and O2 flux near sea-level values.