The objective of this case-control study was to investigate the determinants of maternal stress in mothers of children with autism. Mothers of 31 children with autism from mental health clinics were matched by child age/gender and mother age to 31 mothers of children without mental health problems, drawn from public schools and a primary care unit. Logistic regression models showed that the presence of stress in mothers was primarily associated with having a child with autism. However, poor expression of affect, little interest in people, being an older mother, and having a younger child also contributed to increased stress levels. Although having a child with autism was the main factor responsible for stress, the presence of the other factors further increased maternal stress. The implication is that a subgroup of mothers of children with autism is more prone to experience stress, thus requiring special attention from mental health professionals.