Background Previous research has suggested an increased risk for individuals with phenylketonuria (PKU) of developing depression and other mood disorders. As PKU can disrupt neurotransmitter synthesis via biochemical mechanisms, depressive symptoms are hypothesised to result from neurotransmitter dysregulation. Whilst adherence (or return) to the phenylalanine-restricted diet may resolve or improve symptoms of depression, data to demonstrate a direct relationship between biochemistry and mood in this population are lacking. Methods Thirteen adolescents with early and continuously treated PKU and eight sibling controls were compared in their total reported depressive symptoms. A general executive function assessment was also undertaken in the PKU group. Correlations between depressive symptoms and biochemical markers were examined within the PKU group only. Results Correlational analyses within the PKU group demonstrated strong and significant associations between depressive symptoms and long term exposure to either a high phenylalanine:tyrosine ratio, or low tyrosine. Increasing symptoms of depression were also found to be associated with poorer executive function in the PKU sample. However, both groups of adolescents scored within the normal range in symptoms of depression (p >0.05). Conclusions Significant associations were observed between biochemical markers indicating poorer dietary control and increasing depressive symptoms in a sample of adolescents with early and continuously treated PKU, although symptoms of depression remained within the normal range. An association between depressive symptoms and poorer EF was also demonstrated. Further research is needed to establish whether the depressive symptoms observed in this young population represent an emerging (subclinical) risk for major depressive disorder as they age.