Background: Toxoplasmosis is one of the most common causes of latent infections in humans and animals. Its important clinical aspect is the probable danger of congenital transmission and its severe effects on the fetus. Infection is typically asymptomatic at birth, or is associated with serious neurological or ocular sequelae later in life with a broad spectrum of clinical presentations. Serologic screening detects acute infection in pregnant women which if unrecognized may be transmitted to the unborn. Objective: To investigate serologically the prevalence of toxoplasmosis as a hidden cause of mental retardation (MR) in a sample of children from urban and surrounding rural areas attending the New Children Hospital of Cairo University (Abu Reesh Hospital), Cairo. Material and Methods: The present study was conducted on 200 children diagnosed as MR attending neurology outpatient clinics as a case group; and 200 samples as a control group from non-MR children attending other outpatient clinics with minor complaints such as skin manifestations in dermatology clinic, upper respiratory infections and minor gastrointestinal complaints. Venous blood samples from the two groups of children were serologically tested for specific IgG by indirect hemagglutination test (IHAT). Relevant sociodemographic and clinical data related to the children and their mothers was collected using a designed sheet. Results: Our results showed that the prevalence of toxoplasmosis in the MR children was significantly positive in 84/200 (42.0%) of the case group (P <0.001). The number of positive sera was 35/200 (17.5%) among control group. Associated clinical manifestations in the case group (MR) included convulsions in 53.5%, eye problems in 22.5%, splenomegaly in 16.5% and hepatomegaly in 9.5% of cases. There was no significant difference between urban and rural residences; and relevant risk factors in mothers included history of previous toxoplasmosis (13.5%), history of abortion and still birth (each 36.5%) and premature deliveries (19.5%). History of contact with cats and consumption of undercooked meat rated 58% and 77.7% respectively. Conclusion: Screening females who are at risk for acquired toxoplasmosis is essential, before and during pregnancy to detect Toxoplasma seroconversion. Conversion from negative to positive testing would indicate exposure to infection, requiring the implementation of early treatment of infection to protect the unborn fetuses from transplacental transmission.