Background: The concept of differential susceptibility has challenged the potential meaning of personal traits such as poor ability to regulate emotions. Under the traditional model of diathesis/stress, personal characteristics such as liability to angry outbursts are seen as essentially disadvantageous, emerging under duress in a way that is maladaptive. In contrast, with differential susceptibility, there is the same poorer functioning under adverse conditions but, under favorable conditions, individuals with the trait function "better" than those without it. To date, there have been limited studies on response under positive environments. We used the experimental power of an intervention trial to test the differential susceptibility hypothesis that children with emotional dysregulation would show greater response to an experimentally induced improvement in their parenting environment. Methods: Data were from the SPOKES trial (ISRCTN 77566446), a randomized controlled trial of 112 school children who were 5-6-years old, screened for elevated levels of oppositionality, randomized to parenting groups or control; 109 (97%) were followed-up a year later. Using DSM-IV oppositional-defiant symptoms, children were divided into an Emotionally-Dysregulated type (ED, n = 68) and a Headstrong type (n = 44). The parenting intervention was the Incredible Years program supplemented by positive strategies to use when reading with children. Assessment of conduct problems and parenting was by semistructured interviews. Results: At follow-up, parents of Emotionally-Dysregulated and Headstrong children allocated to the intervention showed significant improvements in their parenting strategies to an equal extent compared to parents in the control group. However, the Emotionally-Dysregulated children showed a significantly greater decrease in conduct problems between intervention and control groups (treatment effect-size 0.84 standard deviations) than the Headstrong (es 0.20 SD), p = 0.04. Conclusions: Using the power of a controlled experiment, this study showed that children who exhibited Emotionally-Dysregulated behavior pretreatment were more responsive to improvements in parental care that were experimentally induced. The findings extend prior work on differential sensitivity in suggesting that children exhibiting irascibility and emotionality may show greater susceptibility to the caregiving environment, and may identify a subset of children who respond better to existing treatments. (Contains 5 tables and 1 figure.)