Background: Early adolescence is a critical time for the development of both internalizing and externalizing disorders. We aimed to investigate whether pituitary volume, an index of hypothalamic-pituitary-adrenal (HPA) axis function, represents a vulnerability factor for the emergence of internalizing and externalizing symptoms during adolescence using a prospective, longitudinal design. Methods: One hundred and fifty-five adolescents completed 3T structural magnetic resonance imaging (MRI), symptom rating scales and a diagnostic interview during early adolescence (M age 12.6 years, SD 0.5 years); symptom rating scales were re-administered approximately three years later (M age 15.2 years). The volume of the pituitary gland was estimated by manually delineating its structure on MR images. The degree to which pituitary volumes prospectively predicted change in internalizing and externalizing symptoms across the two time-points was assessed using hierarchal linear regression, after controlling for the influence of gender, age, pubertal stage and intracranial volume. Results: Larger pituitary volumes prospectively predicted an increase in internalizing, but not externalizing, symptoms from early adolescence to mid-adolescence. Conclusions: This study provides the first evidence that increased pituitary volume might represent a specific vulnerability marker for the development of internalizing symptoms during early to mid-adolescence.