Protein tyrosine phosphatase (PTP)-1B, encoded by the PTPN1 gene, inactivates the insulin signal transduction cascade by dephosphorylating phosphotyrosine residues in insulin signaling molecules. Due to its chromosomal location under a chromosome 20 linkage peak and the metabolic effects of its absence in knockout mice, it is a candidate gene for type 2 diabetes. Recent studies have associated common sequence variants in PTPN1 with type 2 diabetes and diabetes-related phenotypes. We sought to replicate the association of common single nucleotide polymorphisms (SNPs) and haplotypes in PTPN1 with type 2 diabetes, fasting plasma glucose, and insulin sensitivity in a large collection of subjects. We assessed linkage disequilibrium, selected tag SNPs, and typed these markers in 3,347 cases of type 2 diabetes and 3,347 control subjects as well as 1,189 siblings discordant for type 2 diabetes. Despite power estimated at >95% to replicate the previously reported associations, no statistically significant evidence of association was observed between PTPN1 SNPs or common haplotypes with type 2 diabetes or with diabetic phenotypes.