Stress and genetic predisposition are two of the major risk factors for a variety of psychiatric illnesses. Inbred mouse strains are considered useful tools in dissecting the genetic basis of complex disorders. Indeed, mice of the C57BL/6 and BALB/c strains, differing markedly in anxiety behaviours, are among the most widely used in psychopharmacological research. However, there is a paucity of studies investigating the impact of social stress in these two strains. Moreover, whether these two mouse strains exhibit different sensitivities to chronic social defeat stress remains poorly studied. Thus in this study we compared the impact of repeated (10 days) social defeat stress on a variety of behavioural and endocrine parameters including social interaction, locomotor activity, plasma corticosterone, body weight and stress-related physiological parameters in both mouse strains. Given that the duration of stress exposure may differentially affect such responses we also compared stressors of short (Social Defeat-Short; SD-S) and of long (Social Defeat-Long; SD-L) duration. Our results show that although mice from both strains were defeated in both social defeat paradigms, only BALB/c mice displayed social interaction impairments following SD-S, whereas both strains were behaviourally sensitive to SD-L. Moreover, both strains also differed in some of the physiological alterations induced by social defeat stress. Specifically, SD-S did not induce any change in corticosterone levels in either of the two strains, whereas SD-L was able to induce significant changes in C57BL/6 mice only. SD-S induced differential effects on bodyweight gain in both strains, increasing it in C57BL/6 and decreasing it in BALB/c mice, whereas SD-L had no effect. On the other hand, exposure to SD-S resulted in cardiac hypertrophy in C57BL/6 mice and SD-L induced spleen hypertrophy and thymus atrophy in BALB/c mice in addition to decreasing faecal output. Overall, the innately anxious BALB/c mice were more sensitive to social stress than C57BL/6, with differential behavioural and physiological alterations emerging as a function of stress severity. These data suggest different coping strategies to social interaction stress between the two mouse strains. The genetic basis of this stress-resilience/susceptibility warrants further investigation.