In recent years the pace of discovery of genetic associations with type I diabetes (T1D) has accelerated, with the total number of confirmed loci, including the major histocompatibility complex (MHC) region, reaching 43. However, much of the deciphering of the associations at these, and the established T1D loci, has yet to be performed in sufficient numbers of samples or with sufficient markers. Here, 257 single-nucleotide polymorphisms (SNPs) have been genotyped in 19 candidate genes (INS, PTPN22, IL2RA, CTLA4, IFIH1, SUMO4, VDR, PAX4, OAS1, IRS1, IL4, IL4R, IL13, IL12B, CEACAM21, CAPSL, Q7Z4c4(5Q), FOXP3, EFHB) in 2300 affected sib-pair families and tested for association with T1D as part of the Type I Diabetes Genetics Consortium's candidate gene study. The study had approximately 80% power at alpha=0.002 and a minor allele frequency of 0.2 to detect an effect with a relative risk (RR) of 1.20, which drops to just 40% power for a RR of 1.15. At the INS gene, rs689 (-23 HphI) was the most associated SNP (P=3.8 x 10(-31)), with the estimated RR=0.57 (95% confidence interval, 0.52-0.63). In addition, rs689 was associated with age-at-diagnosis of T1D (P=0.001), with homozygosity for the T1D protective T allele, delaying the onset of T1D by approximately 2 years in these families. At PTPN22, rs2476601 (R620W), in agreement with previous reports, was the most significantly associated SNP (P=6.9 x 10(-17)), with RR=1.55 (1.40-1.72). Evidence for association with T1D was observed for the IFIH1 SNP, rs1990760 (P=7.0 x 10(-4)), with RR=0.88 (0.82-0.95) and the CTLA4 SNP rs1427676 (P=0.0005), with RR=1.14 (1.06-1.23). In contrast, no convincing evidence of association was obtained for SUMO4, VDR, PAX4, OAS1, IRS1, IL4, IL4R, IL13, IL12B, CEACAM21 or CAPSL gene regions (http://www.T1DBase.org).