Colorectal cancer (CRC) is the second leading cause of cancer-related death and usually arises from colorectal polyps. Screening and removal of polyps reduce mortality from CRC. Colorectal polyps are known to aggregate in families; however the genetic determinants for risk of polyps are unknown. In addition, it has been shown that nonsteroidal anti-inflammatory drug (NSAID) use decreases the risk of CRC and the incidence and size of polyps. In this study, we used data from the Tennessee Colorectal Polyp Study and the Tennessee-Indiana Adenoma Recurrence Study to evaluate selected genes from the prostaglandin (PG) metabolism and signaling pathways for association with risk of polyps and for interactions with NSAIDs. Our design consisted of discovery and replication phases for a total of 2,551 Caucasian polyp cases and 3,285 Caucasian controls. We carried out multivariable logistic regression to test for association in both the discovery and replication phase and further examined the results with meta-analysis. We detected association signals in the genes PGE receptor 3 (PTGER3) and 15-hydroxyprostaglandin dehydrogenase (HPGD), both strong biologic candidates for influence on polyp risk. We did not observe the previously reported effects and effect modification in PG-endoperoxide synthase 2 (PTGS2), PGE receptor 2 (PTGER2), or PGE receptor 4 (PTGER4), although we did observe a single nucleotide polymorphism in PTGER2 associated with risk of multiple adenomas. We also observed effect modification of the HPGD signal by NSAID exposure.