This study aimed to determine whether different levels of hypoxia affect physical performance during high-intensity resistance exercise or subsequent cardiovascular and perceptual responses. Twelve resistance-trained young men (age, 25.3 ± 4.3 years; height, 179.0 ± 4.5 cm; body mass, 83.4 ± 9.1 kg) were tested for 1 repetition maximum (1RM) in the back squat and deadlift. Following this, participants completed 3 separate randomized trials of 5 × 5 repetitions at 80% 1RM, with 3 minutes rest between sets, in normoxia (NORM; fraction of inspired oxygen [FIO2] = 0.21), moderate-level hypoxia (FIO2 = 0.16), or high-level hypoxia (FIO2 = 0.13) by a portable hypoxic unit. Peak and mean force and power variables were monitored during exercise. Arterial oxygen saturation (SpO2), heart rate (HR), and rating of perceived exertion (RPE) were assessed immediately following each set. No differences in force or power variables were evident between conditions. Similar trends were evident in these variables across each set and across the exercise session in each condition. SpO2 was lower in hypoxic conditions than in NORM, whereas HR was higher following sets performed in hypoxia. There were no differences between conditions in RPE. These results indicate that a hypoxic stimulus during high-intensity resistance exercise does not alter physical performance during repetitions and sets or affect how strenuous exercise is perceived to be. This novel training strategy can be used without adversely affecting the physical training dose experienced and may provide benefits over the equivalent training in NORM.