The deleterious bone effects of mechanical unloading have been suggested to be due to oxidative stress and (or) inflammation. Resveratrol has both antioxidant and anti-inflammatory properties; therefore, the study's objective was to determine whether providing resveratrol in the low supplementation range for a short duration prevents bone loss during mechanical unloading. Mature (6 months old) Fischer 344 × Brown Norway male rats were hindlimb-suspended (HLS) or kept ambulatory for 14 days. Rats were provided either trans-resveratrol (RES; 12.5 mg/kg body mass per day) or deionized distilled water by oral gavage for 21 days (7 days prior to and during the 14 days of HLS). Bone mass was measured by dual energy X-ray absorptiometry. Bone microstructure was determined by microcomputed tomography. HLS of rats resulted in femur trabecular bone deterioration. Resveratrol supplementation did not attenuate trabecular bone deterioration in HLS rats. Unexpectedly, HLS-RES rats had the lowest tibial bone mineral content (P < 0.05), calcium content and lower cortical thickness (P < 0.05), and increased porosity compared with HLS/control rats. Plasma osteocalcin was also lower (P < 0.04) in HLS/resveratrol rats. There were no significant effects on plasma C-reactive protein, a marker of systemic inflammation, or total antioxidant capacity. However, HLS-RES rats showed a negative relationship (r(2) = 0.69, P = 0.02) between plasma osteocalcin and thiobarbituric acid reactive substances, a marker of lipid peroxidation. Based on the results, resveratrol supplementation of 6-month-old HLS male rats had no bone protective effects and possibly even detrimental bone effects.