To evaluate the independent and combined effects of hypoxia (FiO2 = 13.5%) and cold (-20°C) on physiological and perceptual responses to endurance exercise. 14 trained male subjects ( O2max: 64 ± 5mL/kg/min) randomly performed a discontinuous maximal incremental test to exhaustion on a motorized treadmill under four environmental conditions: Normothermic-Normoxia (N), Normothermic-Hypoxia (H), Cold-Normoxia (C) and Cold-Hypoxia (CH). Performance and physiological and perceptual responses throughout exercise were evaluated. Maximal WorkLoad (WL) and WL at lactate threshold (LT) were reduced in C (-2.3% and -3.5%) and H (-18.0% and -21.7%) compared to N, with no interactive (p = 0.25 and 0.81) but additive effect in CH (-21.5% and -24.6%). Similarly, HRmax and Vemax were reduced in C (-3.2% and -14.6%) and H (-5.0% and -7%), showing additive effects in CH (-7.7% and -16.6%). At LT, additive effect of C (-2.8%) and H (-3.8%) on HR reduction in CH (-5.7%) was maintained, whereas an interactive effect (p = 0.007) of the two stressors combined was noted on Ve (C: -3.1%, H: + 5.5%, CH: -10.9%). [La] curve shifted on the left in CH, displaying an interaction effect between the 2 stressors on this parameter. Finally, RPE at LT was exclusively reduced by hypoxia (p < 0.001), whereas TSmax is synergistically reduced by cold and hypoxia (interaction p = 0.047). If compared to single stress exposure, exercise performance and physiological and perceptual variables undergo additive or synergistic effects when cold and hypoxia are combined. These results provide new insight into human physiological responses to extreme environments.