In trained endurance athletes, the ability to defend arterial oxy-hemoglobin saturation (SaO2) during high intensity constant-workload exercise in moderate hypoxia depends in part on the ability to increase minute ventilation (V̇E). Previous data have shown, however, that despite the existence of a substantial amount of ventilatory reserve (V̇Eres) in some cyclists, V̇E surprisingly does not increase during 5km time trials (5kTT) in hypoxia, despite a significant decrease in both SaO2 and mean power output (PTT) from normoxia. PURPOSE: To determine the effect of reducing the work of breathing (Wb) on V̇E, breathlessness (RPB), and PTT during a 5kTT in hypoxia in highly trained cyclists. We hypothesized no change in RPB, while V̇E would increase with an attenuated decrement in SaO2 and PTT from normoxia. METHODS: Fourteen trained male cyclists (V̇O2max = 58.7 ± 4.7 ml·kg-1·min-1) performed a 5kTT under 3 conditions at sea level: ‘CON’ (FiO2 = 0.21), ‘HYP’ (FiO2 = 0.16), and ‘HYP+He’ (FiO2 = 0.16, with balance helium). Esophageal balloons were used to assess Wb in each condition. Inspiratory capacity maneuvers were performed at each km, and flow-volume loop analyses were used to assess the %EFL and V̇Eres. The modified Borg scale (0-10) was used to assess RPB at each km. RESULTS: Wb decreased from HYP to HYP+He by 30 ± 18% (p < 0.01). Despite a substantial V̇Eres throughout CON (52 ± 44 L·min-1), V̇E was not different between CON (117.4 ± 17.9 L·min-1) and HYP (124.8 ± 17.9 L·min-1) but increased during HYP+He (139.5 ± 22.0 L·min-1; p < 0.05). While SaO2 decreased from CON to HYP by 10 ± 1% (p < 0.01), SaO2 increased by 4 ± 1% from HYP to HYP+He (p < 0.01). PTT decreased from CON to HYP (-14.2%; p < 0.01) and increased from HYP to HYP+He (+5.5%; p < 0.01). When comparing HYP to HYP+He, a significant correlation was observed between ΔSaO2 and ΔPTT (r = 0.69; p < 0.05). RPB increased from CON (6.0 ± 2.0) to HYP (7.0 ± 2.0; p < 0.05) and was unchanged from HYP to HYP+He (6.6 ± 2.0). CONCLUSIONS: In moderate hypoxia, a low ventilatory reserve does not limit 5km time trial performance, where by design, individuals are free to adjust power output. The ability to utilize ventilatory reserve while remaining below a critical threshold of perceived breathlessness appears conducive to maintaining aerobic exercise performance in moderate hypoxia.