Investigating etiological processes early in the life span represents an important step toward a better understanding of the development of personality pathology. The current study evaluated the interaction between an individual difference risk factor (i.e., temperament) and a biological risk factor for aggressive behavior (i.e., atypical [larger] rightward hippocampal asymmetry) in predicting the emergence of borderline personality disorder (BPD) and antisocial personality disorder symptoms during early adolescence. The sample consisted of 153 healthy adolescents (M = 12.6 years, SD = 0.4, range = 11.4–13.7) who were selected from a larger sample to maximize variation in temperament. Interactions between four temperament factors (effortful control, negative affectivity, surgency, and affiliativeness), based on the Early Adolescent Temperament Questionnaire—Revised, and volumetric measures of hippocampal asymmetry were examined as cross-sectional predictors of BPD and antisocial personality disorder symptoms. Boys were more likely to have elevated BPD symptoms if they were high on affiliation and had larger rightward hippocampal asymmetry. In boys, low affiliation was a significant predictor of BPD symptoms in the presence of low rightward hippocampal asymmetry. For girls, low effortful control was associated with elevated BPD symptoms in the presence of atypical rightward hippocampal asymmetry. This study builds on previous work reporting significant associations between atypical hippocampal asymmetry and poor behavioral regulation.