Objective: The causal effect relationship between smoking and stress is a subject that invites continuous research.  Hypothetically, investigation of stress biomarkers that are reported to be affected by tobacco intake may give us some explanation of the association between stress and smoking as a habit.  Consequently, the present study aimed to assess the serum level of some stress biomarkers and compare them among smokers and non-smokers in a sample of Egyptian male healthy volunteers. Methods: Fifty-nine subjects were enrolled in the study (29 smokers and 30 non-smokers of matched age and gender). We measured serum levels of cortisol and interleukin-6 (IL-6) using the ELISA technique, and serum levels of α-amylase, triglycerides (TG), and total cholesterol (TC) using colorimetric methods. Results: Serum cortisol levels were decreased in smokers, and IL-6, TG, and TC were significantly higher in smokers than non-smokers, whereas, serum α-amylase did not show a significant difference. Serum cortisol showed to be negatively correlated with serum IL-6 in smokers. Conclusions: The present study assumes that smokers suffer from a state of chronic stress as evidenced by the observed decrease in serum cortisol due to negative feedback effects and increase in levels of serum IL-6, TG, and TC. This in turn enhances the craving to smoke to face stressors and leads to a vicious circuit that smokers fail to quit smoking.