We assessed similarities and differences in self-reported stress (Parenting Stress Index: Short Form [PSI-SF]), patterns of challenging child behavior (Nisonger Child Behavior Rating Form [NCBRF]), and characteristics of autism (Gilliam Autism Rating Scale 2nd Edition [GARS-2]) across two distinct groups of children and young adults 5 to 24 years old: Cornelia de Lange Syndrome (CdLS, n = 25, Mage (SD) = 11.4 (4.7) years), and Down syndrome (DS, n = 23, Mage (SD) = 13.4 (6.0) years). Parents were recruited from the CdLS-USA Foundation and DS parent support groups across the United States. The study focused on identifying specific patterns of (a) parenting stress and (b) challenging behavior and autism-like characteristics in children with CdLS and DS. It was found that parents of CdLS children experienced far more stress than those of children with DS, and the difference could not be explained completely by demographic variables or children’s developmental level. Rather it appears that the especially elevated stress in parents of children with CdLS can be traced in significant part to the children’s high levels of challenging behavior, low levels of pro-social behavior, and self-injury / stereotypy. Additional results revealed that children with CdLS exhibited significantly higher levels of challenging behavior and autism-like characteristics, and lower levels of pro-social behavior, and appropriate communicative behaviors. Multivariate regression showed that optimum prediction of stress for the total sample was yielded by a combination of the child’s elevated self-injury / stereotypy and decreased social interaction skills (R2 = 0.217, R2adj = 0.182, pmodel = 0.004), and the addition of the child’s diagnosis significantly increased predictability, R2 = 0.273, R2adj = 0.223, pmodel = 0.003. The elevated stress in parents of children with CdLS appears to be focused primarily on their children’s specific difficult child behaviors, a factor that was of much less concern to parents of children with DS. Results are discussed in terms of a possible behavioral phenotype for CdLS and future research on early intervention for parenting stress. It is noted that parenting stress in the CdLS sample is so high as to be unmeasurable (i.e., ceiling effect) in a large minority of the parents, and this makes it an urgent priority to develop well-targeted early interventions for parenting stress in these families.