Aim: Research indicates that cigarette smoking is strongly associated with unemployment. However, little is known regarding the underlying mechanisms explaining this relationship. The aim of this study is to examine the role of psychosocial factors as potential mediators between unemployment and smoking. Participants: 4002 non-institutionalised, civilian adults living in the Veneto region of Italy. Design: The study was based on a computer assisted telephone interview (CATI). Linear by linear association tests were used to examine bivariate associations between unemployment, psychosocial factors, and smoking. Logistic regression models were developed to analyse the relationship between unemployment and smoking when adjusting for psychological factors. Results: The odds of smoking among the unemployed was 2.78 times (95% confidence interval (CI) 1.68 to 4.62) greater than that of higher managers and professionals controlling for demographic factors. The relationship between unemployment and smoking weakened (odds ratio 2.41, 95% CI 1.43 to 4.05) when psychosocial factors were entered into the analysis. The odds of the inability to control important things in life was 1.39 times (95% CI 1.11 to 1.75) greater, and the odds of emotional isolation was 1.45 times (95% CI 1.06 to 1.99) greater, among smokers compared to non-smokers controlling, for all other factors. Conclusions: Given that the data were cross sectional, firm conclusions cannot be drawn regarding the causal pathway connecting unemployment and smoking. However, this study suggests that psychosocial factors such as the inability to control and emotional isolation may be plausible mediators for the relationship. C igarette smoking is considered one of the most serious risk factors for chronic diseases worldwide. In populations where smoking has been common for many decades, tobacco use accounts for a large proportion of mortality. Overall, it is thought to be responsible for 26.3% of deaths and 17.1% of disability adjusted life-years (DALYs) among males and 9.3% of deaths and 6.2% of DALYs among females in industrialised nations. Current smoking patterns are estimated to account for 2.4 million deaths each year in the same area.1 Cigarette smoking increases risk for lung cancer, upper aero digestive cancer, several other cancers, heart disease, stroke, chronic respiratory diseases, and a number of other medical conditions. It is responsible for approximately 90% of lung cancer in men and about 70% of lung cancer among women.1-3 The attributable fractions for chronic respiratory diseases and cardiovascular diseases are 56-80% and 22%, respectively.