Transcription factors of the nuclear factor of activated T cells (NFAT) family regulate both immune activation and insulin production. Calcineurin inhibitors (CNIs) target NFAT activation. Hence, CNIs not only prevent organ transplant rejection but also contribute to the development of new-onset diabetes after transplantation (NODAT). Given individual variation in the susceptibility to NODAT, we hypothesized that polymorphisms in the cytoplasmic NFAT (NFATc)4 gene, which is expressed in pancreatic islets, may be associated with NODAT. Haplotype-tagging single-nucleotide polymorphisms (SNPs) of the NFATc4 gene were genotyped in Hispanic renal transplant patients. Cumulative incidences of NODAT were compared between recipients of different NFATc4 genotypes and haplotypes. The Cox proportional hazard model was used to examine risks for NODAT. Nongenetic and genetic characteristics were included in the multivariate risk model. The SNP (rs10141896) T allele was associated with a lower cumulative incidence of NODAT (P=0.02). This is a tagging SNP for one of the five dominant NFATc4 haplotypes, T-T-T-T-G, and CNI-treated recipients with this haplotype had a reduced adjusted risk for NODAT (hazard ratio: 0.45; 95% confidence interval: 0.19-1.01). Conversely, patients homozygous for the C-C-C-G-G haplotype were at an increased risk (hazard ratio: 2.13; 95% confidence interval: 1.01-4.46) for NODAT in subanalysis. Of the nongenetic factors, use of tacrolimus, sirolimus, and older age were associated with increased risk for NODAT. Polymorphisms in the NFATc4 gene may confer certain protection or predisposition for NODAT.