Hormone replacement therapy (HRT) is a potential treatment to relieve symptoms of menopause and prevent the onset of disease such as osteoporosis in postmenopausal women. We evaluated changes in markers of exercise-induced skeletal muscle damage and inflammation (serum CK, serum LDH, and mRNA expression of IL-6, IL-8, IL-15, and TNF-) in postmenopausal women following a high-intensity resistance exercise bout. Fourteen postmenopausal women were divided into two groups: Control, women not using HRT (n=6, 59±4 yr, 63±17 kg), or HRT, women using traditional HRT (n=8, 59±4 yr, 89±24 kg). Both groups performed 10 sets of 10 maximal eccentric repetitions of single-leg extension on the Cybex dynamometer at 60°/s with 20 second rest periods between sets. Muscle biopsies of the vastus lateralis were obtained from the exercised leg at baseline and 4 hours after the exercise bout. Gene expression was determined using RT-PCR for IL-6, IL-8, IL-15, and TNF-. Blood draws were performed at baseline and 3 days post-exercise to measure CK and LDH. Independent t-tests were performed to test group differences (Control vs HRT). A probability level of p0.05 was used to determine statistical significance. We observed significantly greater changes in mRNA expression of IL-6, IL-8, IL-15, TNF- (p0.01) in the Control group compared to the HRT group following the exercise bout. CK and LDH levels were significantly greater post-exercise (p0.01) in the Control group. Postmenopausal women not using HRT experienced greater muscle damage after maximal eccentric exercise indicating a possible protective effect of HRT against exercise-induced skeletal muscle damage.