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It may be difficult to distinguish type 1 diabetes mellitus (T1DM) from type 2 diabetes mellitus (T2DM) in the pediatric population. Autoantibodies may help to differentiate both types of diabetes, but sometimes these are positive in patients with T2DM and negative in patients with T1DM. The human leukocyte antigen (HLA)-DR genotype has been associated with T1DM and with T2DM only in adults and in determined cases.To determine the differences in HLA class II allele frequencies in Mexican children with T1DM and T2DM.We included 72 children with T1DM, 28 children with T2DM, and 99 healthy controls. All were Mexican, and diabetes was diagnosed according to the clinical and laboratory criteria established by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. The HLA-DRB1 typing was performed using polymerase chain reaction–sequence-specific oligonucleotide probe and polymerase chain reaction sequence-specific primers.We found an increased frequency of HLA-DRB1*08 and a decreased frequency of HLA-DRB1*04 in the group with T2DM vs. T1DM [p = 0.0001, odds ratio (OR) = 10.58, 95% confidence interval (CI) = 3–40.8 and p = 0.0006, OR = 0.24, 95% CI = 0.11–0.53, respectively]. No significant differences were found between HLA-DRB1 alleles in T2DM vs. controls. In the group with T1DM, there was a significantly increased frequency of the HLA-DR4 and HLA-DR3 alleles relative to controls (p = 0.0000001, OR = 3.59, 95% CI = 2.2–5.8 and p = 0.00009, OR = 4.66, 95% CI = 2.1–10.3, respectively).There are significant differences in the HLA profile in Mexican children with T1DM and T2DM. HLA typing could play a role in the differentiation between both types of diabetes in this population.