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To investigate whether performing resistance exercise in hypoxia augments physiological and perceptual responses, and if altering work-rate by performing repetitions to failure compared to sub-maximally increases the magnitude of these responses. Twenty male university students (minimum of 2 year resistance training experience) completed four sessions, two in hypoxia (fraction of inspired oxygen [FiO2] = 0.13), and two in normoxia (FiO2 = 0.21). For each condition, session one comprised three sets to failure of shoulder press and bench press (high work-rate session), while session two involved the same volume load, distributed over six sets (low work-rate session). Muscle oxygenation (triceps brachii), surface electromyographic activity (anterior deltoid, pectoralis major, and triceps brachii), heart rate (HR), and arterial blood oxygen saturation were recorded. Blood lactate concentration ([Bla−]) was recorded pre-exercise and 2 min after each exercise. Muscle thickness was measured pre- and post-exercise via ultrasound. Muscle oxygenation values during sets and inter-set rest periods were lower in hypoxia vs normoxia (p = 0.001). Hypoxia caused greater [Bla−] during the shoulder press of failure sessions (p = 0.003) and both shoulder press (p = 0.048) and bench press (p = 0.005) of non-failure sessions. Hypoxia increased HR during non-failure sessions (p