Low load exercise to failure has been shown to elicit muscle hypertrophy similar to high load exercise. However, if the load is very low [i.e. 15% of one repetition maximum (1RM)], the contraction intensity may not disrupt blood flow enough to induce failure. Although unknown, the application of blood flow restriction (BFR) during very low load exercise may be necessary in order to reach failure. PURPOSE: To compare the acute responses associated with a hypertrophic stimulus during lower body exercise using a traditional high load (70% 1RM), very low load (15% 1RM) with no BFR, or in combination with moderate (40% arterial occlusion pressure (AOP)) or high (80% AOP) BFR pressure; coded as 70/0, 15/0, 15/40, and 15/80 respectively. METHODS: 22 participants completed 4 sets of unilateral knee extensions to failure (up to 90 repetitions) with each condition. Muscle thickness (MTh) and maximal voluntary contractions (MVC) were assessed before (Pre), immediately following (Post), and 15 minutes after exercise (15-Post). Electromyography (EMG) amplitude of the rectus femoris (RF) and vastus lateralis (VL) was assessed during the last 3 repetitions of each set. Data presented as mean (SD) with p≤0.05. RESULTS: There was an interaction for MTh, however, follow up tests revealed no differences within time points. Overall, MTh increased from Pre to Post [0.48 (0.17) cm], decreased at 15-post [-0.11 (0.18) cm], but remained elevated over Pre [0.36 (0.07) cm]. There was an interaction for MVC and follow up tests revealed differences at Post [15/80 < 15/0, 15/40, < 70/0] and 15-Post [15/0 < 15/80, 70/0]. All conditions decreased MVC at Post [-111.1 (48) Nm] and increased from Post to 15-Post [79.2 (43.1) Nm]. There was a main effect of condition for RF EMG, with 70/0 being greater than 15/80 [83 (37) vs. 57 (27) %MVC]. For VL EMG, there was a main effect of condition [70/0 > 15/80, 15/40, 15/0] and time [set 1< 2, 3, 4]. Typically, VL EMG was greater for 70/0 [106 (70) %MVC] compared to 15/0 [73 (21)], 15/40 [72 (30)], and 15/80 [64 (21)]. CONCLUSIONS: BFR with a higher pressure seemed to augment the acute muscular response to very low load exercise, making it closer to the response observed during high load exercise. This suggests that a higher BFR pressure may be necessary to induce hypertrophy when resistance training with very low loads.