Background: Many researchers have revealed that health related quality of life (HRQOL) is significantly related to multiple socio-demographic factors in the general population. Only one previous research examined HRQOL in under five children with Down Syndrome (DS). So far, there are no DS-specific or gold standard tools present for this purpose. Objective(s): This study aimed to measure HRQOL in under five children with DS and to investigate its relation to some socio-demographic characteristics of under 5 children with DS and their caregivers. Methods: In a cross-sectional study of 267 under five children with DS, HRQOL was measured with the TNO-AZL Preschool Children Quality of Life (TAPQOL) questionnaire. TAPQOL was translated into Arabic and validated. Sociodemographic data were collected through a validated pre-designed structured interview questionnaire filled by the caregivers (mostly mothers). Results: The study revealed that 59.6%, 37.1% and 3.4% of the studied children had good, fair and poor HRQOL, respectively. Good HRQOL were significantly associated with children age group (1-<1.5 years) (0.000), mothers' age group (<20 years) (0.039), professional work of the father (00.000) and married parents (0.042). These results were statistically significant. Nearly two thirds (62.5%) of the studied children with average socioeconomic status, had good HRQOL. This result was not statistically significant. Conclusion: More than half of the studied sample had good HRQOL. Good HRQOL were significantly associated with children age group (1-<1.5 years), mothers' age group (<20 years), professional work of the father and married parents. The relation between the HRQOL and the socioeconomic class was not significant.