Recent genome-wide association studies have identified several loci that confer an increased risk of colorectal cancer (CRC). We studied the role of the 8q24.21 (rs6983267), 18q21.1 (rs12953717), 15q13.3 (rs4779584), 11q23.1 (rs3802842), 8q23.3 (rs16892766), and 10p14 (rs10795668) risk variants in a series of 995 Dutch CRC cases and 1340 controls. The CRC cases were selected on basis of having a family history of CRC and/or early-onset disease. The detailed clinical and molecular data available on the cases allowed us to examine the relationship between risk variants and clinicopathologic characteristics. We replicated the association with an increased risk of CRC cancer for all loci, except 10p14. The association with the variant on chromosome 15q13.3 was confirmed for the first time. The risks associated with variants in our series were higher (not significant) than those previously reported, consistent with our series reflecting genetic enrichment. Moreover, we show that familial CRC cases possess an increased number of risk alleles compared with solitary CRC cases (early-onset; mean age at diagnosis of 48.5 years). We also identified a significant increase in the number of risk alleles in families with early-onset disease (<or=50 years) compared with late-onset families (>50 years). In solitary CRC patients, enrichment for risk alleles was not observed, suggesting that other causes of increased CRC risk play a role in these cases. Overall, our results suggest that clustering of low-risk variants may explain part of the excess risk in CRC families.