Winchester, LJ, Morris, CE, Badinger, J, Wiczynski, TL, and VanWye, WR. Blood flow restriction at high resistance loads increases the rate of muscular fatigue, but does not increase plasma markers of myotrauma or inflammation. J Strength Cond Res 34(9): 2419-2426, 2020-High-load resistance training and blood flow restriction (BFR) training at low loads both promote protein synthesis and growth through different cell signaling mechanisms. Therefore, co-activation of these pathways could result in a synergistic effect for additional growth enhancement. The purpose of this study was to evaluate how BFR effects performance and physiological responses after an acute bout of high-load barbell squat training. Twelve resistance-trained, college-aged men and women performed 5 sets of barbell squats at 75% of 1 repetition maximum until failure under traditional (TRAD; control) or intermittent BFR conditions. Perceived limb pain and number of repetitions performed were recorded after each set. Blood samples were collected at baseline and 1-hour postexercise after each trial for analysis of myoglobin and interleukin-6 (IL-6). An alpha level of p < 0.05 was used to determine significance. Blood flow restriction trial performance significantly declined at set 3 and was lower than performance during control, whereas control performance did not decrease until set 5. Perceived limb pain was statistically increased with BFR use for the whole trial and was significantly higher with BFR during set 3 than observed during TRAD. Plasma myoglobin and IL-6 were significantly increased after both trials when compared with baseline, but were not significantly different between trials. Intermittent BFR use during high-load barbell squats increases the rate of muscular fatigue and perceived limb pain, but does not increase muscular damage or inflammatory response. Data obtained from this study can be used by fitness professionals as a means of potentially enhancing the rate of muscular hypertrophy.