The aim of this study was to determine the association between sexuality following TBI and demographic, injury-related, and postinjury variables (age, gender, time since injury, posttraumatic amnesia duration, independence in activities of daily activities (ADL), antidepressant use, depression, and self-esteem). Methods: Participants included 986 individuals with predominantly moderate to severe TBI, who completed the Brain Injury Questionnaire of Sexuality (BIQS), the Hospital Anxiety and Depression Scale, and the Rosenberg Self-Esteem Scale and an ADL assessment on 1 or more occasions, providing a total of 1673 assessments across 1, 2, 3, 5, 10, and 20 years postinjury. Results: Being depressed, older in age, at shorter time postinjury, and less independent in ADL significantly predicted poorer overall BIQS scores as well as the Sexual Functioning subscale score. Poorer Relationship Quality and Self-esteem scores on the BIQS were predicted by older age at injury and higher levels of depression. Lower Mood score on the BIQS was associated with shorter posttraumatic amnesia duration, younger age, and higher levels of depression. Self-esteem was associated positively with sexuality outcome. Conclusions: Therapeutic interventions for sexuality need to focus on depression where indicated and self-esteem and address specific barriers to social participation and opportunities for sexual contact in individuals who are less independent in ADL.