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Interrelationships between insulin-like growth factors (IGFs), hyperinsulinaemia, diabetes, and colorectal cancer (CRC) indicate involvement of IGFs in colorectal tumorigenesis. We investigated the CRC risk associated with 24 single nucleotide polymorphisms (SNPs) in 9 genes related to the IGF pathway and an IGF1 19-CA repeat polymorphism. Variants were selected from literature and genotyped in toenail DNA from 3,768 subcohort members and 2,580 CRC cases from the Netherlands Cohort Study, which has a case-cohort design (n = 120,852). We used the follow-up period 1986-2002. Eighteen SNPs were unequivocally associated with selected endpoints in the literature and unfavorable alleles were aggregated into a genetic sum score. Cox regression showed that a higher genetic sum score significantly increased CRC risk at all subsites, except the rectum, in men (highest vs. lowest tertile: HR for CRC = 1.36, 95% CI: 1.11, 1.65; P-trend = 0.002). Single SNPs (except the IGF1 SNP rs5742694) were not associated with risk. Models including the total number of IGF1 19-CA repeats showed CRC risk was halved at all subsites in women carrying <38 repeats but not >38 repeats (</=36 versus 38 repeats: HR for CRC = 0.44; 95% CI: 0.33, 0.58; P-trend < 0.001). These findings support a role for variants in IGF-related genes in colorectal tumorigenesis.