Background: Alpha defensins were known to have broad spectrum potent antimicrobial acdtivities. Objectives: To evaluate plasma alpha-defensin 1- 3 levels in smoker and non-smoker male patients with type 2 diabetes mellitus (T2DM). Methodology: The subjects included 50 consecutive current smoker men with T2DM attending the outpatient clinic, Zagazig University Hospitals (Egypt), matched for age and diabetes duration with 50 consecutive non-smoker men with T2DM and 100 healthy men (50 smokers; 50 non-smokers). Associations between α-defensin plasma levels and characteristics of participants were evaluated. Results: Plasma levels of α-defensins were significantly higher in smokers compared with non-smokers in diabetic and non-diabetic subjects (P<0.001 for all comparisons). Ten characteristics of participants that significantly correlated with α-defensins were further analyzed using stepwise multiple linear regression. The final model included four variables explaining 47.0% of the variation in α-defensin level. Presence of diabetes alone accounted for 32.6% of the variation. However, 40.1% of the variation in α-defensins could be explained by including current smoking. Conclusion: Plasma α-defensin 1-3 is elevated in patients with T2DM, and current smoking is combined with a further elevation. Given the known association between α-defensin and serious complications of diabetes, results of the current study should have important clinical implications in the management of patients with T2DM who smoke or think about smoking.