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High intensity, short rest protocols have become increasingly popular within the fitness industry. Such protocols can elicit extensive muscle damage and oxidative stress; thus the purpose of this study was to examine markers of muscle tissue damage and inflammation along with testosterone responses to a high intensity (75% 1RM), short rest resistance exercise protocol and sex-specific effects. Nine resistance trained men (age: 23.6 ± 3.5 years, weight: 77.8 ± 8.8 kilograms, height: 172.4 ± 4.0 cm, body fat 9.3 ± 3.3 %) and nine resistance trained women (age: 22.9 ± 2.0 years, weight: 68.6 ± 10.4 kilograms, height: 168.6 ± 9.4 cm, body fat 13.6 ± 3.3 %) participated. The protocol consisted of a descending pyramid scheme starting at 10 for three major lifts. No significant sex interactions were seen with testosterone or IL-6. There were significant sex interactions observed in myoglobin (IP) and CK (IP, +60, +24). Men demonstrated significant increases in testosterone (IP, +15), myoglobin (IP, +15, +60, +24), IL-6 (IP), and CK (IP, +60, +24). Women demonstrated significant increases in myoglobin (IP, +15, +60), IL-6 (IP), and CK (+24). There were no significant increases observed in women for testosterone. Women demonstrated a greater absolute increase in myoglobin per kilogram of fat free mass than men (+15, +60) indicating a sufficient degree of muscle damage. Both men and women demonstrated significant muscle damage with a high intensity, short rest protocol with different hormonal and immune responses, most likely mediated through differing signaling cascades.