Abstract: Type 1 diabetes (T1D) is a chronic autoimmune disorder caused by the destruction of the β-cells of pancreas. Genetic and environmental factors are involved in the pathogenesis of T1D. This study aimed to determine the association between Human Leukocyte Antigens (HLA) Class II alleles encoding DR and DQ haplotypes and T1D in Saudi children. Human Leukocyte Antigens were analyzed by polymerase chain reaction sequence-specific oligonucleotide technique (PCR-SSO). The results indicated a significant association between T1D and DRB1*04:05 (P 0.001; OR = 3.14; 95% CI: 1.59-6.16) and DRB1*04:02 (P 0.010; OR = 2.87; 95% CI: 1.33-6.22) alleles. While DQB1*06:03 (P 0.013) and DRB1*13:01 (p 0.0067) alleles were significantly unassociated with T1D. The frequencies of the haplotypes DRB1*04:05-DQA1*03:01-DQB1*03:02 (P 0.004), DRB1*04:02-DQA1*03:01-DQB1*03:02 (P 0.005), and DRB1*04:02-DQA1*03:01-DQB1*02:02 (p 0.008) were significantly higher in T1D patients. On the contrary, the haplotype DRB1*13:01-DQA1*01:03-DQB1*06:03 (P 0.034; OR: 0.12; 95% CI: 0.014-0.94) was significant higher in control. Moreover, a significant association was observed in DRB1*04:05-DQA1*03:02 (P 0.006; OR: 3.47; 95% CI: 1.46-8.21) and DRB1*04:05-DQA1*05:01 (P 0.016; OR: 4.26; 95% CI: 1.36-13.35) haplotypes. In addition, thehaplotypeDRB1*04:05-DQB1*03:02 (P<0.001; OR: 8:54; 95% CI: 2.85-25.60) revealed the highest associated haplotype to T1D. DRB1*04:02-DQB1*03:02 haplotype was present in one fourth of T1D patients (n=24) as compared with a 10th control (P 0.022; OR: 2.71; 95% CI: 1.21-6.06). The results also showed that the haplotype DRB1*04:02-DQB1*02:01 was present in 13.54% T1D patients and 4.17 % of controls (P 0.042, OR: 3.60; 95 percent CI: 1.13-11.48). Our investigation showed that the studied alleles and haplotypes have a highly significant association with T1D. It could be considered that the susceptible risk factors for developing T1D in Saudi children would be DRB1*04:02 and DRB1*04:05 alleles as well as DRB1*05:05-DQA1*03:01-DQB1*03:02 haplotypes. On the other hand, the DQB1*06:03, DRB1*13:01, DRB1*10:01 alleles and DRB1*13:01-DQA1*01:03-DQB1*06:03 haplotype may be considered as protective factors for T1D.