Abstract Family history is a major risk factor for colorectal cancer (CRC), since individuals with an affected first-degree relative have more than twice as high risk of developing this malignancy than the general population. Hereditary factors are estimated to underlie approximately 35% of CRC, but germline mutations in high-penetrance genes, including MLH1, MSH2, APC, and MYH account for only ∼5% of all cases. According to the “common disease - common variant” concept, much of the uncharacterized inheritance is caused by large numbers of common low-penetrance variants. Genome-wide association studies have recently identified ten independent chromosomal loci that predispose to CRC with allelic odds ratios of ∼1.2. Although the individual effect of each variant is modest, the proportion of CRC attributed to the ten variants is large due to the high frequencies of risk alleles in the population. Paradoxically, it has been estimated that they explain only a small proportion of the empirical excess familial risk of CRC. The aim of this study was to evaluate the combined contribution of the ten low-penetrance loci on familial CRC and other clinical characteristics. The analyzed variants were rs6983267 at 8q24, rs4779584 at 15q13, rs4939827 at 18q21, rs16892766 at 8q23, rs10795668 at 10p14, rs3802842 at 11q23, rs4444235 at 14q22, rs9929218 at 16q22, rs10411210 at 19q13, and rs961253 at 20p12. Our Finnish population-based series of CRC samples consisted of 826 cases, of which genotypes in the ten loci and registry-based clinical data was available. There were 37 cases known to carry high-penetrance germline mutations, and these were excluded from the analysis. The remaining cases consisted of 97 patients with at least one affected first-degree relative and 691 with no affected first-degree relatives. The overall number of risk alleles (0-20) was counted for each individual, after which their association with familial CRC and other clinical characteristics was analyzed by logistic regression. We observed a linear association between increasing numbers of risk alleles in the ten loci and odds of having familial CRC (P=0.006). With each one unit increase in the number of risk alleles, the odds of having an affected family member increased by a factor of 1.16 (95% CI 1.04-1.30). Furthermore, we estimated which proportion of the familial aggregation of CRC can be attributed to the ten loci, by calculating excess familial risk. This was performed based on age-, sex-, and calendar period incidence rates in the first-degree relatives of the probands and in the general population of Finland. The ten low-penetrance variants explain approximately 9% (upper 95% CI 19%) of the variance in familial risk of CRC. Our results provide robust evidence to support the previous indirect estimations that these low-penetrance variants account for only a small proportion of familial CRC and emphasize the need to characterize the remaining inherited predisposition to this malignancy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3864.