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The process of returning to work (RTW) after multiple injuries is lengthy. Prospective studies with follow-up times of up to 5 years are necessary but lacking. The aim of this study was to describe the trajectory of RTW and to examine the factors that predicted RTW over 5 years for patients with multiple injuries using a prospective cohort design.One-hundred one patients aged 18 years to 67 years who had been admitted to a trauma referral center with a New Injury Severity Score >15 starting January 2002 through June 2003 were included. The follow-up rate at 5 years was 79%. Outcomes were assessed 6 weeks after discharge and at 1 year, 2 years, and 5 years postinjury. The instruments used to assess patient status were the Short Form 36, the World Health Organization Disability Assessment Schedule II cognitive subscale, a Cognitive Function Scale, and the Brief Approach/Avoidance Coping Questionnaire. Repeated measures analyses of categorical correlated data were applied.Patient's mean age was 34.5 years (SD, 13.5); 83% were men and 25% had a university or college education; 66% were blue-collar workers. Mean New Injury Severity Score was 35.1 (SD, 12.7). RTW rates were 28% at 1 year, 43% at 2 years, and 49% at 5 years postinjury. There were differences among patients in RTW status, and personal factors and physical and psychosocial functioning. Predictors of RTW were as follows: measurement occasion, education (high/low), coping, and physical and cognitive functioning. The proportion of unexplained variation between subjects in the models was 31% to 55%.Of the patients included in this study, 49% achieved RTW, and 23% received full disability benefits. Higher education; better physical, social, and cognitive functioning; and coping strategies all predicted RTW.