Self-esteem, the value we place on ourselves, has been associated with effects on health, life expectancy, and life satisfaction. Correlated with self-esteem is internal locus of control, the individual's perception of being in control of his or her outcomes. Recently, variations in self-esteem and internal locus of control have been shown to predict the neuroendocrine cortisol response to stress. Cumulative exposure to high levels of cortisol over the lifetime is known to be related to hippocampal atrophy. We therefore examined hippocampal volume and cortisol regulation, to investigate potential biological mechanisms related to self-esteem. We investigated 16 healthy young (age range 20-26 years of age) and 23 healthy elderly subjects (age range 60-84 years). The young subjects were exposed to a psychosocial stress task, while the elderly subjects were assessed for their basal cortisol regulation. Structural Magnetic Resonance Images were acquired from all subjects, and volumetric analyses were performed on medial temporal lobe structures, and whole brain gray matter. Standardized neuropsychological assessments in the elderly were performed to assess levels of cognitive performance, and to exclude the possibility of neurodegenerative disease. Self-esteem and internal locus of control were significantly correlated with hippocampal volume in both young and elderly subjects. In the young, the cortisol response to the psychosocial stress task was significantly correlated with both hippocampal volume and levels of self-esteem and locus of control, while in the elderly, these personality traits moderated age-related patterns of cognitive decline, cortisol regulation, and global brain volume decline.