CXCR-2 is a receptor of interleukin-8, which is involved in acute and chronic inflammatory processes. Polymorphisms in the CXCR2 gene have been associated with chronic inflammatory conditions. The aim of this study was to investigate whether the +785(C/T), +1208(T/C), and +1440(G/A) single-nucleotide polymorphisms (SNPs) in the CXCR2 gene, as well as their haplotypes, are associated with susceptibility to periodontitis in Brazilians. DNA was extracted from the buccal epithelial cells of 487 individuals (control = 215; periodontitis = 272). The SNPs were investigated using the sequence-specific primer-polymerase chain reaction method. Associations between the polymorphisms and subject phenotypes were analyzed using the chi-squared statistical test, followed by univariate and multivariate logistic regression modeling. Haplotypes were reconstructed using the expectation-maximization algorithm, and differences in haplotype distribution between the groups were analyzed to estimate genetic susceptibility for periodontitis development. Univariate and multivariate analysis revealed that age, skin color, and smoking status were associated with periodontitis. The +1440 GG genotype was shown to be protective against periodontitis in both univariate and multivariate analysis (odds ratio [OR](adjusted) = 0.42; 95% confidence interval [CI] = 0.19, 0.96). A similar relevant result for the +1440 GG was obtained in an alternative analysis considering a subgroup containing only white nonsmokers (OR = 0.37; 95% CI = 0.15, 0.92). White nonsmokers with the CTG/TCG haplotype appeared to be genetically protected against the development of periodontitis (OR = 0.29; 95% CI = 0.09, 0.89), while those carrying the CTG/TCA haplotype were more susceptible to the development of periodontitis (OR = 2.08; 95% CI = 1.24, 3.51). In conclusion, the +1440 SNP and some haplotypes are associated with periodontitis in Brazilian individuals.