Histone methyltransferase (HMT) enzymes that methylate the lysine of histones are involved in chromatin-mediated gene expression. Previously, we reported that a novel polymorphism of SUV39H2, the HMT that is required for the methylation of H3-K9, was associated with an increased risk of lung cancer in Koreans. The retinoblastoma protein-interacting zinc finger gene RIZ (PRDM2) is also a member of a histone/protein-methyltransferase superfamily, and the inactivation of RIZ in many cancers was detected as frameshift mutations, hypermethylation and missense mutations. In this study, we show the association of RIZ polymorphisms with the risk of lung cancer. In a hospital-based study of 335 lung cancer patients and 335 age- and gender-matched healthy controls, 120 polymorphisms of RIZ were screened. Of the 120 genotyped single nucleotide polymorphisms (SNPs), 42 SNPs were selected for the statistical analysis based on their frequency (>5%) and linkage disequilibrium [LD; only a representative SNP was analyzed if there were absolute LDs (r2 = 1)]; this resulted in three LD blocks. The +92337G>A and +95701C>A polymorphisms showed a statistically significant association with the reduced risk of lung adenocarcinomas after correcting the P values for multiple testing [for carrying one variant allele versus none, adjusted odds ratio (aOR) = 0.55 (95% CI = 0.38-0.78), corrected P = 0.04; aOR = 0.54 (95% CI = 0.38-0.77), corrected P = 0.02, respectively]. One haplotype (Ht5) in LD block 3 of RIZ was significantly associated with the reduced risk of lung adenocarcinomas (aOR = 0.28, 95% CI = 0.13-0.58) as well as overall lung cancer (aOR = 0.50, 95% CI = 0.30-0.82). This study suggested that RIZ polymorphisms may be important predictive markers for lung cancer susceptibility.