Research for the causes of diabetic nephropathy has focused on the study of the affected familial disease clusters. The polymorphism in apolipoprotein E (ApoE) has been linked to the development of diabetic nephropathy (DN) in association with hyperlipidemia. The aim of this study was to evaluate the association of this condition with ApoE gene polymorphism connected with DN in diabetic Egyptian subjects. One hundred and thirty-five patients were enrolled in the study, they were divided into three groups: 45 diabetic patients; 45 DN patients and 45 healthy control group. Clinical examination and routine laboratory investigations with serum lipids and urinary microalbumin were done. Peripheral blood leukocytes from all were examined by the polymerase chain reaction for polymorphisms in ApoE gene. Our results revealed significant difference between Apo E genotype frequencies among all studied groups. Genotypes e2e3 and e2e4 were reported to be significantly higher in diabetes as compared to control individuals while genotype e3e3 was higher in control as compared to diabetes. Among the entire diabetic group e2e3 was highly detected in DN. Regarding allelic frequency e2 allele was significantly detected in DN patients as compared to diabetic patients and it was the lowest in control individuals. In conclusion Apo e2 mutations may have a role in increasing the development of DN among the Egyptian individuals. V C 2015 IUBMB Life, 68(1): [58][59][60][61][62][63][64] 2016