The potential effect of parental separation during early adolescence on adolescent externalizing and internalizing problems was investigated in a longitudinal sample of adolescents (n = 1274; mean age = 16.27; 52.3% girls). Pre-separation mental health problems were controlled for. Building on a large number of studies that overall showed a small effect of parental separation, it was argued that separation may only or especially have an effect under certain conditions. It was examined whether child temperament (effortful control and fearfulness) moderates the impact of parental separation on specific mental health domains. Hypotheses were derived from a goal-framing theory, with a focus on goals related to satisfying the need for autonomy and the need to belong. Controlling for the overlap between the outcome domains, we found that parental separation led to an increase in externalizing problems but not internalizing problems when interactions with child temperament were ignored. Moreover, child temperament moderated the impact of parental separation, in that it was only related to increased externalizing problems for children low on effortful control, whereas it was only related to increased internalizing problems for children high on fearfulness. The results indicate that person-environment interactions are important for understanding the development of mental health problems and that these interactions can be domain-specific.