A common single nucleotide polymorphism (SNP), rs6983267, at 8q24.21 has recently been shown to associate with colorectal cancer (CRC). Three independent SNP association studies showed that rs6983267 contributes to CRC with odds ratios (OR) of 1.17 to 1.22. Here, we genotyped a population-based series of 1,042 patients with CRC and 1,012 healthy controls for rs6983267 and determined the contribution of SNP to CRC in Finland, using germ line DNA, as well as the respective cancer DNA in heterozygous patients. The comprehensive clinical data available from the 1,042 patients and their first-degree relatives enabled us to thoroughly examine the possible association of this variant with different clinical features. As expected, a significant association between the G allele of rs6983267 and CRC [OR, 1.22; 95% confidence interval (CI), 1.08-1.38; P = 0.0018] was found, confirming the previous observations. A trend towards association of the G allele with microsatellite-stable cancer (OR, 1.37; 95% CI, 1.02-1.85; P = 0.04) and family history of cancers other than CRC was seen (OR, 1.20; 95% CI, 1-1.43; P = 0.05). Four hundred and sixty-six GT heterozygotes identified in this study were analyzed for allelic imbalance at rs6983267 in the respective cancer DNA. One hundred and one tumors showed allelic imbalance (22%). The risk allele G was favored in 67 versus 34 tumors (P = 0.0007). This finding implicates that the underlying germ line genetic defect in 8q24.21 is a target in the somatic evolution of CRC.