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Anecdotally, it is believed that the deadlift exercise brings about greater levels of central fatigue than other exercises; however no empirical evidence exists to support this view. Additionally, little is known about the acute endocrine response to heavy deadlift exercise and how this may differ to other similar compound exercises. Therefore, the aim of this study was to identify and compare the acute, neuromuscular and endocrine responses to squat and deadlift exercise. Ten resistance trained males completed 8 sets of 2 repetitions at 95 % of one repetition maximum. Maximum voluntary isometric knee extensor force (MVIC), along with measures of central (voluntary activation (VA) and surface electromyography (EMG)) and peripheral (electrically evoked control stimulus) fatigue were made prior to and 5 and 30 min post-exercise. Additionally, salivary testosterone and cortisol were measured at these same time points. MVIC was reduced after the completion of both exercises (p = 0.007) however no difference between exercises was evident. Similarly, although VA changed over time (p = 0.0001) no difference was observed between exercises. As a measure of peripheral fatigue, force from the control stimulus changed over time (p = 0.003) with a greater decrease evident after the squat (p = 0.034). EMG was reduced over time (p = 0.048) but no difference was seen between exercises. No change was seen in testosterone and cortisol. Even though a greater absolute load and larger volume-load was completed for the deadlift, no difference in central fatigue was evident between the two compound exercises. The greater peripheral fatigue observed after squat exercise may be due to the greater work completed by the quadriceps with this exercise. These results suggest that separate periodization, tapering and programming considerations may be unnecessary when using the squat and deadlift to develop muscular strength.