Osteosarcoma is a primary bone malignancy that typically occurs during the pubertal growth spurt. Only a few small association studies have evaluated common germ line variation in individuals with osteosarcoma. The 8q24 chromosomal region contains several loci that are associated with risk of many different cancers. We conducted an association study of common single-nucleotide polymorphisms (SNPs) across 8q24 to explore the role this region may play in osteosarcoma risk. We genotyped 214 tag SNPs in 99 osteosarcoma cases and 1430 controls (65 controls from a hospital-based case-control study and 1365 controls from a population-based study). Additive, dominant and recessive genetic models were evaluated using unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Analyses of nine SNPs previously associated with cancer did not show strong statistically significant associations. Of the remaining 205 SNPs, 7 were statistically significant (P </= 0.05) in one or more genetic models; the most significant association was observed for the additive effect of the minor allele at rs896324 (OR 1.75, 95% CI 1.13-2.69, P = 0.01). This study suggests that several SNPs in 8q24 may be associated with osteosarcoma, but the susceptibility observed was modest. Future large studies of osteosarcoma genetic risk factors are warranted to improve our understanding of the genetic contribution to this cancer of adolescents and young adults.