Most colorectal cancers originate from polyps, however, only a small proportion of polyps progress to carcinomas. Genome-wide association studies have identified multiple single-nucleotide polymorphisms (SNPs) in relation to colorectal cancer. Using these genetic risk variants, we evaluated whether colorectal cancer genetic factors may determine certain polyp phenotypes with different malignant potential. We analyzed 20 SNPs in 15 colorectal cancer susceptibility loci in a case-control study including 2473 cases (1831 with adenomas and 642 with hyperplastic polyps only) and 4019 controls. These patients were recruited from participants who received colonoscopy at two major hospitals in Nashville. A weighted genetic risk score (wGRS) was created to measure the cumulative association of multiple SNPs with polyp subtypes. Thirteen SNPs in 10 loci showed a statistically significant (P < 0.05, n = 9) or marginally significant (P < 0.10, n = 4) association with the risk of adenomas or hyperplastic polyps in the same direction as reported previously for colorectal cancer. A dose-response relation was observed between the wGRS and adenoma risk [per-allele odds ratio (OR) = 1.15, 95 confidence interval (CI): 1.10-1.20, P (trend) = 7.3×10(-10)], with the association stronger for advanced than non-advanced adenomas (P (heterogeneity) = 0.038), for multiple adenomas than a single adenoma (P (heterogeneity) = 0.039), and for proximal than distal adenomas (P (heterogeneity) = 0.038) and for adenomas diagnosed at younger than older age (P (heterogeneity) = 0.031). A similar, but weak association between the wGRS and hyperplastic polyps was also observed (OR = 1.11, 95% CI: 1.04-1.18, P (trend) = 0.002). These findings suggest that genetic factors play a significant role in the development of polyps with different malignant potential.