The objective of the study was to investigate change and predictors of change in health-related quality of life (HRQoL) in relatives of patients with severe traumatic brain injury (TBI) during rehabilitation, and to analyse associations between changes in HRQoL and symptoms of anxiety and depression. The Vitality (VT), Mental Health (MH), Social Function (SF) and the Role Emotional (RE) scales from the Short Form 36, and the anxiety and depression scales from the Symptom Checklist-90 – Revised were used. Of the 62 relatives, 24.6% experienced a reliable improvement on the VT scale, 53.2% on the MH scale, 27.4% on the SF scale and 16.1% on the RE scale. Of the relatives, 24.0% experienced clinically significant change (CSC) on the VT scale, 19.6% on the MH scale, 21.6% on the SF scale, and 19.2% on the RE scale. Relatives’ age and higher patient Glasgow Coma Scale score predicted the experience of CSC in RE, and change on the Functional Independence Measure in patients predicted CSC on the MH scale. Improvements in VT as well as MH were associated with improvement in symptoms of anxiety and depression, and improvement in SF was associated with improvement in symptoms of depression. About one-fifth of the sample experienced a CSC on one of the four HRQoL measures. Relatives experiencing CSC tended to be related to patients who showed more improvement during rehabilitation. Improvements in HRQoL were associated with improvements in symptoms of anxiety and depression.