Measuring health-related quality of life (HRQoL) has an important role in the comprehensive assessment of patient recovery following traumatic brain injury (TBI). We examined the validity of domain and summary scores derived from the Medical Outcomes Survey 36-Item Short Form Health Questionnaire (SF-36) as outcome measures for TBI in a prospective study of 514 patients with a range of functional impairment (Glasgow Outcome Scale-Extended [GOSE] scores 3-8). Item scaling criteria for the eight domain scores were tested and principal component analysis was used to examine if physical and mental component summary scores were valid. External validity was assessed by comparison with GOSE. Mean response, variance, and distribution of the items were largely equivalent, and item-own scale correlations corrected for overlap all exceeded the threshold for equivalent contribution to domain scores and convergent validity. All corrected item-own scale correlations were greater than the respective item-other correlations indicating no scaling failures, and reliability coefficients for the domain scores were high and substantially more than the inter-domain correlations. Overall, criteria for summing items into domain scores were satisfied, and there was a significant relationship of increasing score with more favorable GOSE class across all domains. However, there were floor and/or ceiling effects in four of the eight domains, and principal component analysis of the domain scores demonstrated only a unidimensional structure to the data. We conclude that individual SF-36 domain scores are valid measures of HRQoL in TBI patients, but that the physical and mental component summaries should be interpreted with caution.