Driven by findings that human papillomavirus (HPV)-induced degradation of p53 differs by a TP53 polymorphism at codon 72 (Pro72Arg), past studies of TP53 genetic variants and cervical cancer have focused on this nonsynonymous polymorphism, with mixed results. We analyzed common single nucleotide polymorphisms (SNP) across the TP53 locus in a population-based nested case-control study in Guanacaste, Costa Rica. We evaluated 11 SNPs, including Pro72Arg (rs1042522), among 1,281 women: 465 with cervical intraepithelial neoplasia grade 3/cancer (CIN3+), 380 with HPV persistence (median, 25 months), and 436 random population controls. We combined HPV persistence and CIN3+ into one case group because they did not differ in TP53 genotypic frequencies and calculated odds ratios and 95% confidence intervals (CI) for individual SNPs and inferred haplotypes. We observed that proline at codon 72 was associated with increased risk of CIN3+/persistence compared with population controls. Relative to GG (Arg), the CG (Pro/Arg) and CC (Pro) genotypes had a 1.3-fold (95% CI, 0.99-1.6) and 1.8-fold (95% CI, 1.2-2.7) increased risk, respectively (P(trend) < 0.01). rs12951053 and rs1642785 were also associated with CIN3+/persistence (P (trend), 0.05 and 0.04, respectively), as was a haplotype containing the codon 72 variant (rs1042522), rs12951053, rs1642785, and rs12947788 (odds ratio, 1.6; 95% CI, 1.1-2.3 versus the most common haplotype, which comprised the major alleles for all 11 SNPs). Although genetic variation in TP53 might affect the natural history of HPV and cervical cancer, further work is needed to elucidate the possible mechanism.