Background: Clinical and epidemiological data indicate that Helicobacter pylori (H. pylori) are acquired during childhood and remains for the life time of the host. Patients with physical and mental disabilities may be particularly exposed to this microorganism, because of different dietary, abilities, living, and sanitary condition. Objectives: The current study aimed to investigate the prevalence of H. pylori infection among institutionalized patients with Down syndrome and mental retardation. Patients and Methods: Seventy five institutionalized patients with Down syndrome and mental retardation, with the age range of < 10 to 50 years were selected from welfare Center, an institute for caring mental retardation and Down syndrome patients. Seventy five out patients were also included as controls too. The control population was from the same geographical area as the study group, and had comparable socioeconomic features. Sanitary condition and personal hygiene of both the intervention and control groups were considered. Serum immunoglobulin G (IgG) produced in response to H. pylori infection was measured, with the Helori-test IgG with 92% sensitivity and 95% specificity; urea breath test (UBT) was also done for all. Results: The differences between the groups were compared by t-test and X 2 test. Seropositivity for H. pylori was significantly higher in patients with Down syndrome and mental retardation than in those of the control group (P < 0.001) as the socioeconomic features did not differ between the two groups, this can be a strong consideration of the validity of this comparison (the current study showed that out of 75 specimens, 41 cases were positive by Elisa test; accordingly, UBT test results were positive too). Conclusions: The current study indicated that H. pylori infection occurs at a higher rate in patients with Down syndrome and mental retardation. This may provide more reasons to control the transmission of H. pylori among them.