Mental retardation (MR) is a major health problem affecting 3% of the population. It results from the interaction of many genes and non-genetic factors. However, in up to 60% of patients the aetiology remains unclear. The aim of the study is to examine the association of birth defects and MR, taking into consideration the type of birth defect, level of MR, co-occurrence of MR with other developmental disabilities, genetic and biological risk factors. A case control study was conducted on 300 children with MR from December 2006 to December 2007. They were referred to the Human Genetics Department, Medical Research Institute, University of Alexandria, for diagnosis and genetic counseling. For comparison, 506 normal control groups were randomly selected. The cases were 156 males (54%) and 135 females (46%), the difference was not statistically significant. Out of 300 studied cases, 72 children (24%) had various chromosomal aberrations, while the remaining 228 (76%) had single gene disorder. From these groups 66 children had another coexisting DDS (25 with CP, 15 had VL, 10 with autism; 10 HL and 6 had epilepsy). Mild MR (MMR) was more prevalent among all the studied cases than severe MR (SMR), there was significant association between SMR and birth defects (OR= 1.85, CI: 1.05-3.27). Birth defects occurred in 180 children (40 children with Down syndrome, 1 with sex chromosomal defect, 3 with other chromosomal anomalies, and the remaining 136 with non-chromosomal abnormalities). There was significant association between children with Down syndrome and birth defects (OR=10; CI: 1-242.25). Birth defects were present in 41 children with MR and other coexisting DDs. Also, it was found that all children with different birth defects had significant association with MR, (OR= 87.21; CI: 40.38-196.31). These MR risks tended to be the largest among infants born with heart and central nervous system defects. There was significant association between low birth weight (OR = 3.57; CI: 1.91-6.65), preterm (OR= 9.63; CI: 2.21-47.84), and parental consanguinity (OR= 4.19; CI: 2.9-6.06) and the occurrence of MR. This study high-lights the role of prenatal factors in the origin of many DDS especially MR and suggests that a sizable proportion of DDS may be caused by insults occurring early in embryologic development.