Chronic inflammation is an established risk factor for colorectal cancer (CRC), and polymorphisms in genes regulating inflammatory processes appear to alter the risk for neoplasia and the efficacy of nonsteroidal anti-inflammatory drugs in CRC chemoprevention. We examined the association between selected inflammation gene polymorphisms and CRC risk. In a large population-based case-control study with 1,795 CRC cases and 1,805 controls from the German DACHS study, we evaluated 5 putative functional inflammatory pathway polymorphisms in PRODH, PTGS1 and UBD genes. PTGS1 G213G was significantly associated with an increased CRC risk [odds ratio (OR), 1.19; 95% confidence interval (CI), 1.03–1.39; p = 0.02] comparing minor allele carriers with major allele homozygotes. This risk estimate was consistent across locations and stages of CRC (range of ORs, 1.15–1.20). Carriage of the minor allele of UBD I68T was significantly associated with advanced stages of CRC and with CRC below 65 years of age (OR, 1.23; 95% CI, 1.04–1.45; p = 0.02 and OR, 1.32; 95% CI, 1.05–1.67; p = 0.02, respectively). Our results support a role of variants in inflammatory pathway genes in CRC susceptibility and progression.