Type 1diabetes is one of the most common chronic childhood illnesses. Alleles or genetic variants associated with type 1 diabetes provide either susceptibility to or protection from the disease within a given environmental background.The genetic makeup with the balance between susceptibility and protection alleles determines the age of onset of type 1 diabetes. The population recruited in this study included 96 Egyptian families with one or more index diabetic child or adolescent who are attending outpatient clinic in Diabetes, Endocrinology and Metabolism Paediatrics Unit (DEMPU), at Cairo University Children Hospital. The tested loci included: HLA DR (IDDM1), INS gene (IDDM 2) and CTLA-4 gene (IDDM 12). Healthy unrelated subjects were included in the study to reflect the frequency of the studied loci in the general population; 94 subjects for INS -23/Hph1 A>T polymorphisms, 110 subjects for 49A>G CTLA-4 polymorphisms and 157 subjects for HLA DR typing. They were subjected to history taking, clinical examination and genetic studies; INS -23/Hph1 A>T polymorphisms and 49A>G CTLA-4 polymorphisms were defined using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). HLA DR typing was performed on 43 families only using SSOP invitrogen UK Kit. The INS -23/Hph1 T allele is overrepresented in the 3 diabetic family groups (patients, non diabetic siblings and parents) as compared to the control group (p < 0.001). Comparing patients to normal controls, the T allele is considered a risk factor for the development of T1D (OR= 3.5). Genetic frequencies of CTLA4 49 A>G polymorphisms in type 1 diabetic patients, parents, non diabetic siblings and controls showed no statistically significant difference. DRB1*04 and DRB1*03/ DRB1*04 showed significantly higher frequency in patients as compared to controls (P= <0.001, OR=7.3 at 95%CI (4.2-12.5)]) and p<0.001, OR=20.5 at 95%CI (7.8-53.7)] respectively. On the other hand, DRB1*15 and DRB1*13 showed low frequency in patients as compared to controls (OR=0.33 at 95%CI (0.12-0.96), P=0.03) and [P=0.02, OR= 0.38 at 95%CI (0.17-0.87)] respectively. We conclude that DRB1*04 and DRB1*03/ DRB1*04 genotypes are considered susceptibility genotypes to T1D and confers 7 and 20 folds increase in risk of development of T1D respectively. DRB1*15 and DRB1*13 confers relative protection of T1D in Egyptian population.