Workplace downsizing and closure have been considered natural experiments that strengthen causal inference when assessing the association between unemployment and health. Selection into unemployment plays a lesser role among those exposed to severe workplace downsizing. This study compared mortality for individuals unemployed from stable, downsized, and closed workplaces with a reference group unexposed to unemployment. We examined nationally representative register data of residents of Finland aged 25-63 years in 1990-2009 (n = 275,738). Compared with the control group, the hazard ratio for substance use-related mortality among men unemployed from stable workplaces was 2.43 (95% confidence interval (CI): 2.22, 2.67), from downsized workplaces 1.85 (CI: 1.65, 2.08), and from closed workplaces 2.16 (CI: 1.84, 2.53). Among women, the corresponding estimates were 3.01 (CI: 2.42, 3.74), 2.39 (CI: 1.75, 3.27), and 1.47 (CI: 1.09, 1.99). Unemployment from stable workplaces was associated with mortality from psychiatric and self-harm-related conditions. However, mortality due to ischemic heart disease and other somatic diseases decreased for those unemployed following closure. The results indicate that selection mechanisms partially explain the excess mortality among the unemployed. However, substance-use outcomes among men and women, and fatal accidents and violence among men, might be causally associated with unemployment.