PURPOSE: The authors compared the effects of active preconditioning with local and systemic hypoxia during submaximal cycling. METHODS: On separate visits, 14 active participants completed 4 trials. Each visit was composed of 1 preconditioning phase followed, after 40 minutes of rest, by 3 x 6-minute cycling bouts (intensity = 85% of critical power; rest = 6 min). The preconditioning phase consisted of 4 x 5-minute cycling bouts at 1.5 W.kg-1 (rest = 5 min) in 4 conditions: control (no occlusion and normoxia), blood flow restriction (60% of total occlusion), HYP (systemic hypoxia; inspired fraction of oxygen = 13.6%), and blood flow restriction + HYP (local and systemic hypoxia combined). RESULTS: During the preconditioning phase, there were main effects of both systemic (all P < .014) and local hypoxia (all P </= .001) on heart rate, arterial oxygen saturation, leg discomfort, difficulty of breathing, and blood lactate concentration. Cardiorespiratory variables, gross efficiency, energy cost, and energy expenditure during the last minute of 6-minute cycling bouts did not differ between conditions (all P > .105). CONCLUSION: Local and systemic hypoxic stimuli, or a combination of both, during active preconditioning did not improve physiological responses such as cycling efficiency during subsequent submaximal cycling.