Objectives: Although individuals with traumatic brain injury (TBI) often report higher levels of social isolation, little is known about the factors influencing their self-perception of loneliness. The aim of the current study was to investigate the relationship between loneliness, social network size, and personality variables (neuroticism and extraversion) after TBI, and in particular whether specific personality variables mediate the relationship between social network size and perception of loneliness. Methods: Here, we assessed self-reported loneliness, personality variables, and social network size of 24 individuals with moderate-to-severe TBI and 41 healthy comparison participants. We then carried out a mediation analysis to examine whether personality variables mediated the relationship between loneliness and social network size. Results: Our results indicate that individuals with TBI reported higher levels of loneliness and neuroticism, but there was no group difference in social network size or extraversion. The mediation analysis revealed that the association between social network size and loneliness was mediated by neuroticism, but not by extraversion. Conclusions: Our findings show that neuroticism is an intervening variable in the relationship between social network size and self-perception of loneliness in individuals with moderate-to-severe TBI, and presents a new possible target for clinicians and rehabilitators seeking to address reports of loneliness and social isolation in TBI. (JINS 2019, 25, 266–274)