Defective apoptosis signaling by the Fas pathway has carcinogenic implications. We analyzed 123 pediatric patients with osteosarcoma for Fas single nucleotide polymorphisms: 2 of the promoter region (-1377 G>A and -670 A>G) and 2 of the coding region (exon 3 18272 A>G and exon 7 22628 C>T). As a comparison group, we used 510 adults without a history of cancer. We found an increased risk of osteosarcoma associated with the heterozygous genotype Fas exon 3 AG (genotype frequency 19.5% in cases vs. 12.0% in controls, P=0.028; adjusted odds ratio=1.6, 95% confidence interval=0.9-2.7], and this association was more pronounced in non-Hispanic whites (20.6% in cases vs. 10.1% in controls, P=0.014; adjusted odds ratio=2.3, 95% confidence interval=1.2-4.6). Additionally, the frequency of the variant allele (exon 3 G) was significantly higher in cases than in controls for both the entire group and non-Hispanic whites (P=0.046 and P=0.030, respectively). We found no significant association between osteosarcoma risk and the other Fas polymorphisms. This study suggests an association between the Fas exon 3 A>G polymorphism and osteosarcoma risk; however, further study is needed with pediatric controls and a larger sample size.