Previous studies have shown that creatine supplementation reduces muscle damage and inflammation following running but not following high-force, eccentric exercise. Although the mechanical strain placed on muscle fibers during high-force, eccentric exercise may be too overwhelming for creatine to exert any protective effect, creatine supplementation may protect skeletal muscle stressed by a resistance training challenge that is more hypoxic in nature. The purpose of this study was to examine the effects of short-term creatine supplementation on markers of muscle damage (i.e., strength, range of motion, muscle soreness, muscle serum protein activity, C-reactive protein) to determine whether creatine supplementation offers protective effects on skeletal muscle following a hypoxic resistance exercise test. Twenty-two healthy, weight-trained men (19-27 years) ingested either creatine or a placebo for 10 days. Following 5 days of supplementation, subjects performed a squat exercise protocol (5 sets of 15-20 repetitions at 50% of 1 repetition maximum [1RM]). Assessments of creatine kinase (CK) and lactate dehydrogenase activity, high-sensitivity C-reactive protein, maximal strength, range of motion (ROM), and muscle soreness (SOR) with movement and palpation were conducted pre-exercise and during a 5-day follow up. Following the exercise test, maximal strength and ROM decreased, whereas SOR and CK increased. Creatine and placebo-supplemented subjects experienced significant decreases in maximal strength (creatine: 13.4 kg, placebo: 17.5 kg) and ROM (creatine: 2.4 degrees , placebo: 3.0 degrees ) immediately postexercise, with no difference between groups. Following the exercise test, there were significant increases in SOR with movement and palpation (p < 0.05 at 24, 48, and 72 hours postexercise), and CK activity (p < 0.05 at 24 and 48 hours postexercise), with no differences between groups at any time. These data suggest that oral creatine supplementation does not reduce skeletal muscle damage or enhance recovery following a hypoxic resistance exercise challenge.