Retirement, temporary unemployment and never being employed were associated with higher mortality in a population-based prospective cohort study of 282,364 participants aged 18–65 years in the US National Health Interview Survey from 2001–2013. A total of 12,645 participants died during a mean follow-up of 8.2 years. An increased all-cause mortality risk was evident for participants who were retired (HR 1.27; 95% CI 1.17–1.37), temporarily unemployed (HR 1.76; 95% CI 1.67–1.86), or never employed (HR 1.63; 95% CI 1.47–1.81) compared with employed participants. Conditions associated with increased mortality risk included cancer, cardiovascular disease, chronic lower respiratory disease, diabetes and kidney disease.