The purpose of this study was to compare the acute muscular response with resistance exercise between the following conditions [labeled (% one-repetition maximum/% arterial occlusion pressure)]: high-load (70/0), very low-load (15/0), very low-load with moderate (15/40), and high (15/80) blood flow restriction pressures. Twenty-three participants completed four sets of unilateral knee extension to failure (up to 90 repetitions) with each condition, one condition per leg, each day. Muscle thickness and maximal voluntary contraction (MVC) were measured before (Pre), immediately after (Post-0), and 15 min after (Post-15) exercise and electromyography (EMG) amplitude during exercise. Pre to Post-0 muscle thickness changes in cm [95% CI] were greater with 15/40 [0.57 (0.41, 0.73)] and 15/80 [0.49 (0.35, 0.62)] compared to 70/0 [0.33 (0.25, 0.40)]. Pre to Post-0 MVC changes in Nm [95% CI] were higher with 15/40 [-127.0 (-162.1, -91.9)] and 15/80 [-133.6 (-162.8, -104.4)] compared to 70/0 [-48.4 (-70.1, -26.6)] and 15/0 [-98.4 (-121.9, -74.9)], which were also different. Over the first three repetitions, EMG increased across sets, whereas in the last three repetitions it did not. EMG was also different between conditions and was generally greater during 70/0. Repetitions decreased across sets reaching the lowest for 70/0, and for very low loads decreased with increased pressure. In trained participants exercising to failure, lower load and the application of restriction pressure augment changes in muscle thickness and torque. The EMG amplitude was augmented by load. Training studies should compare these conditions, as the results herein suggest some muscular adaptations may differ.