The aim of this study was to determine prognostic factors for medical and productivity costs, and return to work (RTW) during the first two years after trauma in a clinical trauma population. Methods This prospective multicentre observational study followed all adult trauma patients (�18 years) admitted to a hospital in Noord-Brabant, the Netherlands from August 2015 through November 2016. Health care consumption, productivity loss and return to work were measured in questionnaires at 1 week, 1, 3, 6, 12 and 24 months after injury. Data was linked with hospital registries. Prognostic factors for medical costs and productivity costs were analysed with log-linked gamma generalized linear models. Prognostic factors for RTW were assessed with Cox proportional hazards model. The predictive ability of the models was assessed with McFadden R 2 (explained variance) and c-statistics (discrimination). Results A total of 3785 trauma patients (39% of total study population) responded to at least one follow-up questionnaire. Mean medical costs per patient (€9,710) and mean productivity costs per patient (€9,000) varied widely. Prognostic factors for high medical costs were higher age, female gender, spine injury, lower extremity injury, severe head injury, high injury severity, comorbidities, and pre-injury health status. Productivity costs were highest in males, and in patients with spinal cord injury, high injury severity, longer length of stay at the hospital and patients admitted to the ICU. Prognostic factors for RTW were high educational level, male gender, low injury severity, shorter length of stay at the hospital and absence of comorbidity.