Oxidative stress has recently been identified as a pivotal pathogenetic factor of bone loss in mice, but its importance in humans is not clear. We aimed to investigate the association between urinary 8-iso-PGF(2 alpha) levels, a major F(2)-isoprostane and a reliable in vivo biomarker of oxidative stress, and bone mineral density (BMD), and to study whether vitamin E in the form of serum alpha-tocopherol, a scavenger of peroxyl radicals, modifies the association. In 405 men, urinary 8-iso-PGF(2 alpha) and serum alpha-tocopherol were measured at age 77 years and BMD at age 82 years. One SD increase in 8-iso-PGF(2 alpha) corresponded to an approximately 2-4% decrease in average adjusted BMD values of total body, lumbar spine, and proximal femur (all P<0.001). Serum alpha-tocopherol levels seemed to modify the association between urinary 8-iso-PGF(2 alpha) and BMD. Men with alpha-tocopherol levels below the median combined with high oxidative stress, i.e., 8-iso-PGF(2 alpha) above the median, had 7% (95% CI 3-11%) lower BMD at the lumbar spine and 5% (95% CI 2-9%) lower BMD at the proximal femur. In elderly men high oxidative stress is associated with reduced BMD, which is more pronounced in individuals with low serum levels of the antioxidant vitamin E.