Brain tumors have previously been associated with the Li-Fraumeni syndrome that often is caused by p53 germ line mutations. Therefore, we investigated if polymorphisms of p53 were associated with an increased risk of meningioma and glioma and integrated the polymorphism analyses with detailed information on family history of cancer. In a population-based case-control study, DNA was extracted from 205 glioma and 164 meningioma cases identified during 2000 to 2002 in Sweden and from 374 controls selected randomly from the general population, stratified on age, sex, and geographic region. The Swedish Cancer Registry confirmed a cancer in family members in 86% of cases and controls that reported a family history of cancer. p53 single nucleotide polymorphism (SNP) analyses were done on three SNPs from the promoter region, codon 72 in exon 4, and intron 6. Overall, no associations were found for any of the SNPs. Analyses of the combinations of the three SNPs were also done. The CC-CG-CC-specific polymorphism combination was associated with an odds ratio (OR) of 1.36 [95% confidence interval (95% CI), 0.68-2.72] for glioma and 1.36 (0.64-2.88) for meningioma. When restricting the analyses to cases and controls with a positive family history of cancer, the corresponding results were OR of 3.62 (95% CI, 1.05-12.48) for glioma and 5.69 (1.81-17.96) for meningioma. This study is novel in suggesting an increased risk of brain tumors when the analysis is restricted to those with a history of cancer in the family. However, we cannot rule out the possibility that these results are due to chance.