Abstract Most neuropsychiatric disorders, including stress-related mood disorders, are complex multi-parametric syndromes. Diagnoses are therefore hard to establish and current therapeutic strategies suffer from significant variability in effectiveness, making the understanding of inter-individual variations crucial to unveiling effective new treatments. In rats, such individual differences are observed during exposure to a novel environment, where individuals will exhibit either high or low locomotor activity and can thus be separated into high (HR) and low (LR) responders, respectively. In rodents, a long-lasting, psychosocial, stress-induced depressive state can be triggered by exposure to a social defeat procedure. We therefore analyzed the respective vulnerabilities of HR and LR animals to long-lasting, social defeat-induced behavioral alterations relevant to mood disorders. Two weeks after four daily consecutive social defeat exposures, HR animals exhibit higher anxiety levels, reduced body weight gain, sucrose preference, and a marked social avoidance. LR animals, however, remain unaffected. Moreover, while repeated social defeat exposure induces long-lasting contextual fear memory in both HR and LR animals, only HR individuals exhibit marked freezing behavior four weeks after a single social defeat. Combined, these findings highlight the critical involvement of inter-individual variations in novelty-seeking behavior in the vulnerability to stress-related mood disorders, and uncover a promising model for posttraumatic stress disorder.