Nasal polyposis (NP) is a chronic inflammatory disease. Several genes play major roles in the pathophysiology of the disease. We analyzed RYD5 gene polymorphisms to determine the effect of these variants or their genetic combinations on NP. We genotyped the RYD5 gene in 434 participants (196 patients with NP and 238 controls). Data were analyzed with SPSS, SNPStats, and multifactor dimensionality reduction (MDR) software. We genotyped 10 single-nucleotide polymorphisms (SNPs) in the RYD5 gene. RYD5 (+152G>T) (p.Gly51Va) has not been reported previously. The PolyPhen and PROVEAN predicted the missense mutation as deleterious, but sorting intolerant from tolerant (SIFT) did not. In the genotype analysis, we found that four SNPs (RYD5 [-264A>G], [-103G>A], [+57-14C>T], and [+66A>G]) were significantly associated with NP. The individuals with combined genotypes of six risk alleles (RYD5-264G, -103A, +13C, +57-14T, +66G, and +279T) had significantly higher risks for NP compared with the ones with one or four risk alleles. Haplotype analysis revealed that the two haplotypes were associated with risk of NP. As indicated by MDR analysis, RYD5 (-264A>G and -103G>A) and RYD5 (-264A>G, -177C>A, and -103G>A) were the best predictive combinations and they had the highest synergistic interaction on NP. In addition, RYD5 (+13C>T) was significantly associated with increased risk of both NP with asthma and NP with allergy and asthma. Some SNPs and their combinations in the RYD5 gene are associated with increased probability for developing NP. We emphasize the importance of genetic factors on NP and NP-related clinical phenotypes.