Background: Having children with intellectual disability can be stressful for most parents. Currently there are very few studies focusing on parenting stress among mothers of children with Down syndrome (DS) in Asia. The present study examined the level of parenting stress experienced by Malaysian mothers of children with DS and evaluated the child and maternal factors that contributed to parenting stress based on Hill's ABC-X Model (Hill 1949). Methods: We conducted a cross-sectional study of mothers of children with DS between the ages of 2-12 years during February-June 2008 in Kedah, a state in Peninsular Malaysia. We used self-administered questionnaires to gather data on parenting stress, child's birth history and current behavioural problems, as well as the maternal sociodemographic characteristics, coping styles and psychological well-being. Parental Stress Scale (PSS) was used to assess parenting stress. Measures of child's behavioural problem using Pediatric Symptom Checklist, mother's coping style using Carver "et al". (1989 ) COPE inventory and their psychological well-being using Lovibond and Lovibond (1995) DASS21, a scale assessing depression, anxiety and stress were also carried out. Results: The 147 mothers who participated in the study had an average age of 43.1 years (SD = 7.6 years), of whom 94.6% were married, 57.1% had secondary level education and 28.6% were working outside their home. Based on PSS, mean parenting stress was 37.6 (SD = 8.1). Parenting stress was significantly higher among mothers who reported having children with behavioural problems. However, parenting stress was modified by positive coping styles and negative maternal psychological well-being. The final model based on hierarchical regression analysis identified maternal depression and lack of acceptance as significant predictors of parenting stress rather than child's behavioural problems. Conclusion: Mean parenting stress among mothers of children with DS significantly differed by behavioural problems in their children. Parenting stress is also significantly correlated with frequent use of acceptance, religious and optimist coping styles, and presence of maternal depressive, anxiety and stress symptoms. However, hierarchical regression analysis identified maternal depression and lack of acceptance of having a child with DS as the most significant predictors of parenting stress in these mothers.