BACKGROUND: Smoking is a strong risk factor of metabolic syndrome. Zinc α2-glycoprotein (ZAG) is a protein involved in metabolic syndrome. This study aims to investigate the effect of smoking on plasma ZAG levels and its relations to metabolic syndrome. MATERIALS AND METHODS: A group of 41 cigarette smokers and 47 non-smokers were enrolled. ZAG levels were measured to correlate to participantsʼ demographic and metabolic parameters. RESULTS: Plasma ZAG levels of smokers were higher than those of controls (P < 0·0001). Plasma ZAG levels were positively correlated with male gender (P = 0·0002), number of cigarettes smoked per day (P < 0·0001), smoking duration in years (P < 0·0001), smoking index (P < 0·0001) and nicotine dependence score (P < 0·0001). In the multiple regression analysis, smoking was a strong independent factor affecting plasma ZAG levels (P = 0·0034). Plasma ZAG levels elevated progressively with the number of metabolic syndrome components (P = 0·0143). In the multiple regression analysis, plasma ZAG was an independent factor for metabolic syndrome. CONCLUSIONS: Plasma ZAG levels are high in smokers and correlate with metabolic syndrome. Our results indicate ZAG is an independent risk factor, but also interacted with smoking, for the metabolic syndrome.