The role of non-HLA single nucleotide polymorphisms from a panel of candidate genes in genetic susceptibility to type I diabetes (TID) among Filipinos was examined by PCR/SSOP typing of 90 patients and 94 controls, previously typed for the HLA class I and class II loci. We report the association of CTLA-4 A49G variation (cytotoxic T-lymphocyte associated-4) to TID among Filipinos, consistent with some but not all previous reports in other ethnic groups. The G allele frequency (0.61 versus 0.45, P=0.003) and GG genotype frequency (0.42 versus 0.22, P=0.004) were each increased in patients compared to controls, respectively. Among Filipinos, the CTLA-4 genotypes are associated with disease only in the presence of the predisposing DR3, 4, and 9 haplotypes (P=0.012). Compared to the AA genotype, the increased risk of diabetes predisposition is greatest in genotype GG bearing the DR susceptible alleles (DR3, 4, and 9) (odds ratio=4.6, P=0.001), demonstrating that non- HLA loci, acting in concert with HLA, can play potent roles in modifying susceptibility to TID.