Background: Sex hormone deprivation derived from menopause may affect exercise-induced muscle damage (EIMD). No studies have previously evaluated this response between postmpenopausal and premenopausal eumenorrheic women over the menstrual cycle. Hypothesis: Postmenopausal women will present higher EIMD markers than premenopausal women, especially in comparison with the menstrual cycle phases where sex hormone concentrations are higher. Study Design: Cross-sectional study. Level of Evidence: Level 3. Methods: Thirteen postmenopausal and 19 eumenorrheic women, all of them resistance-trained, performed an eccentric squat-based exercise. The postmenopausal group performed 1 bout of exercise, while the eumenorrheic group performed 3 bouts coinciding with the early follicular, late follicular, and mid-luteal phases ot their menstrual cycle. Muscle soreness, countermovement jump, creatine kinase (CK), myoglobin, lactate dehydrogenase, interleukin-6, tumor necrosis factor-α, and C-reactive protein were evaluated before and postexercise. Results: The expected differences in sex hormones were observed between groups ( P < 0.001) according to their reproductive status. Postexercise increases in CK, myoglobin, and muscle soreness (168.2 ± 45.5 U/L, 123.1 ± 41.5 µg/L, and 20.7 ± 21.3 mm, respectively) were observed in comparison with baseline (136.2 ± 45.5 U/L, 76.9 ± 13.8 µg/L, and 2.7 ± 4.2 mm, respectively). Myoglobin values at baseline in postmenopausal women were higher compared with premenopausal women in the aforementioned menstrual cycle phases, respectively (62.8 ± 8.2, 60.4 ± 7.2, and 60.1 ± 10.6 µg/L; P < 0.001 for all comparisons), which was supported by large effect sizes (0.72-1.08 standardized d units). No postexercise differences were observed between groups in any markers ( P > 0.05). Conclusion: Despite higher resting levels of myoglobin and lower strength values in postmenopausal than in premenopausal women, EIMD was similar between both reproductive profiles. This suggests a potential benefit of being physically active despite aging and sex hormone deprivation. Clinical Relevance: Sex hormone deprivation derived from menopause seems not to influence muscle damage reponse to eccentric exercise in resistance-trained postmenopausal women.