Myocellular stress with high-frequency blood flow restricted resistance exercise (BFRRE) was investigated by measures of heat shock protein (HSP) responses, glycogen content and inflammatory markers. Thirteen participants (24±2 years [mean±SD], 9 males) completed two 5-day-blocks of 7 BFRRE sessions, separated by 10 days. Four sets of unilateral knee extensions to failure at 20% of 1RM were performed. Muscle samples obtained before, 1h after the first session in the first and second block ("Acute1" and "Acute2"), after 3 sessions ("Day4"), during the "Rest Week", and at 3 ("Post3") and 10 days post-intervention ("Post10"), were analyzed for HSP70, αB-crystallin, glycogen (PAS staining), mRNAs, miRNAs, and CD68+ (macrophages) and CD66b+ (neutrophils) cell numbers. αB-crystallin translocated from the cytosolic to the cytoskeletal fraction after Acute1 and Acute2 (p<0.05), and immunostaining revealed larger responses in type I than type II fibers (Acute1, 225±184% vs. 92±81%, respectively, p=0.001). HSP70 was increased in the cytoskeletal fraction at Day4 and Post3, and immunostaining intensities were more elevated in type I than in type II fibers at Day4, (206±84% vs. 72±112%, respectively, p<0.001), during the Rest Week (98±66% vs. 42±79%, p<0.001) and at Post3 (115±82% vs. 28±78%, p=0.003). Glycogen content was reduced in both fiber types; but most pronounced in type I, which did not recover until the Rest Week (-15-29%, p≤0.001). Intramuscular macrophage numbers were increased by ~65% post-intervention, but no changes were observed in muscle neutrophils. We conclude that high-frequency BFRRE with sets performed till failure stresses both fiber types, with type I fibers being most affected. © 2021 the American Physiological Society