The aim of this study was to evaluate cognitive function 10 years after moderate-severe traumatic brain injury (TBI) and to investigate the associations among cognitive function, depression, and health-related quality of life (HRQoL). In this prospective cohort study, with measurements at 3, 6, 12, 18, 24, 36, and 120 months post-TBI, patients 18–67 years of age (n = 113) with moderate-severe TBI were recruited. Main outcome measures were depression (Center for Epidemiologic Studies-Depression Scale [CES-D]), subjective cognitive functioning (Cognitive Failure Questionnaire [CFQ]), objective cognitive functioning, and HRQoL (Medical Outcomes Study 36-Item Short Form Health Survey [SF-36]). Fifty of the initial 113 patients completed the 10 year follow-up. Twenty percent showed symptoms of depression (CES-D ≥ 16). These patients had more psychiatric symptoms at hospital discharge (p = 0.048) and were more often referred to rehabilitation or nursing homes (p = 0.015) than non-depressed patients. Further, they also had significantly lower scores in six of the eight subdomains of the SF-36. The non-depressed patients had equivalent scores to those of the Dutch norm-population on all subdomains of the SF-36. Cognitive problems at hospital discharge were related with worse cognitive outcome 10 years post-TBI, but not with depression or HRQoL. Ten years after moderate-severe TBI, only weak associations (p < 0.05) between depression scores and two objective cognitive functioning scores were found. However, there were moderate associations (p < 0.01) among depression scores, HRQoL, and subjective cognitive functioning. Therefore, signaling and treatment of depressive symptoms after moderate-severe TBI may be of major importance for optimizing HRQoL in the long term. We did not find strong evidence for associations between depression and objective cognitive functioning in the long term post-TBI. Disease awareness and selective dropping out may play a role in long-term follow-up studies in moderate-severe TBI. More long-term research is needed in this field.