Background: Both smoking and obesity increase mortality, however, only few studies have considered premature death. The joint effect of smoking and obesity is less studied. The aim of this study was to examine the joint associations of smoking and obesity with all-cause and cancer mortality among midlife employees. Methods: Baseline mail surveys among employees of the City of Helsinki, Finland, during 2000-2002 include data on smoking (never-, ex-, moderate and heavy), BMI (non-obese, obese), and covariates (N = 8960, response rate 67%). Data were linked with register data on mortality until 2013. The final sample included 6437 employees. Cox proportional hazard models were used. Finally synergistic interaction effect was examined. Results: Adjusting for age and gender, non-obese heavy smokers had an elevated risk of all-cause mortality (HR 2.98, 95% CI 2.05–4.32). The joint association of obesity and smoking with all-cause mortality was stronger (HR 3.46, 95% CI 1.87–6.40), but there was no synergistic interaction (Synergy Index 0.9). Non-obese heavy smokers had an elevated cancer mortality (HR 2.94, 95% CI 1.79–4.82). The joint association of obesity and smoking with cancer mortality was stronger (HR 4.57, 95% CI 2.14–9.76) suggesting a synergistic interaction (Synergy Index 1.6, NS). Ex-smokers’ risk of death was not elevated irrespective of their weight status. Conclusions: Smoking increases the risk of death, and obesity strengthens this association. Quitting smoking, especially among obese people, may reduce premature mortality.