Insulin-like growth factors (IGF) have been associated with risk of common human cancers, but the association between IGFs and pancreatic cancer risk is unclear. To determine whether genetic variations of IGF modify pancreatic cancer risk, we compared the frequency of six single nucleotide polymorphisms of IGF1 and IGF2 in a large-scale case control study. Single nucleotide polymorphisms were investigated using the TaqMan method in 892 patients with pancreatic ductal adenocarcinoma and 783 healthy controls who were recruited from The University of Texas M. D. Anderson Cancer Center from 2000 to 2007. Cases and controls were frequency matched by age (+/-5 years), race, and sex. Risk factor information was collected using direct interviews. We estimated odds ratios (OR) and 95% confidence intervals (95% CI) using unconditional multivariate logistic regression models. A haplotype of IGF1 gene containing the 3'-UTR Ex4 -177 G>C G allele had a significantly lower frequency in cases (0.027) than in controls (0.041; P = 0.039). A statistically significant joint effect of the IGF1 3'-UTR Ex4 -177 G>C C allele and diabetes on pancreatic cancer risk was observed. The OR (95% CI) were 1.07 (0.81-1.42), 2.12 (1.53-2.93), and 5.69 (2.63-12.3) for individuals who had the CC/CG genotype alone, diabetes alone, or both factors, respectively, compared with subjects without either of the two factors with adjustment for other risk factors. The IGF2 3'-UTR Ex4 -233C>T TT genotype was significantly associated with a reduced risk of pancreatic cancer (OR = 0.07; 95% CI = 0.01-0.57; P = 0.013). The polymorphic variants of the IGF genes may serve as a susceptibility factor for pancreatic cancer.