Background. Low bone mineral density (osteopenia) is encountered in children with acute lymphoblastic leukemia (ALL) before, during and after treatment. Prior experience with alendronate, an oral bisphosphonate, demonstrated high tolerability and evident clinical efficacy. However, concerns have been expressed about the long-term safety and utility of such agents in children. Procedure. Of 217 children with ALL treated on Dana Farber Cancer Institute protocols 69 received alendronate for a mean of 87 weeks after dual energy X ray absorptiometry (DXA). DXA was repeated following completion of alendronate, and again 5-9 years later in a subgroup of 32 children. Lumbar spine areal bone mineral (LS aBMD) Z scores were obtained and values corrected for height, age and weight (HAW) were calculated for subjects 3-18 years of age. Results. Almost 80% (N=172) of the children remain in continuous complete remission at a mean of 14.5 years from diagnosis. Of those who receive alendronate, which was almost uniformly well tolerated, 7/69 (10.3%) relapsed compared to 19/89 (21.3%) who did not receive the drug. The mean unmodified LS aBMD Z score rose from -1.78 to -0.47. This gain was statistically significant for both unmodified (p <0.0001) and HAW corrected Z scores -1.32 to -0.42; p <0.0001). There was a modest median loss of LS aBMD (Z score 0.045) subsequently in the subgroup (N=32) of subjects on long-term follow up. Discussion. Alendronate appears to be well tolerated and moderately effective in osteopenic children with ALL. Whether it offers protection against relapse of leukemia needs further study.