Objective. To evaluate the effects of lifestyle modification and metformin on fetuin-A in metabolic syndrome (MetS) as defined in 2006 by the International Diabetes Federation (IDF). Methodology. Forty MetS subjects were randomly assigned to treatment with placebo (n=20) or metformin (n=20) in addition to lifestyle modification for 12 weeks. Results. All 40 participants completed the study. After 12 weeks, both groups had significant reductions in weight (p<0.001), body mass index (BMI) (p<0.001), waist circumference (WC) (p<0.001), systolic blood pressure (SBP) (p<0.001), and diastolic blood pressure (DBP) (p<0.001). The placebo group also had significant improvement in fasting plasma glucose (FPG) (p<0.001) and C-reactive protein (CRP) (<0.05). Weight, BMI, WC, FPG, 2-hour postprandial glucose (2h-PPG), high density lipoprotein cholesterol (HDL-C), triglycerides (TG) and fetuin-A in the metformin group decreased significantly compared to the placebo group. Reduction of plasma fetuin-A was significantly associated with TG in the metformin group. Conclusion. Lifestyle modification and treatment with metformin for 12 weeks improved cardio-metabolic risk factors in MetS and reduced fetuin-A levels. Further investigations are required to confirm the effects of lifestyle modification and metformin after an extended follow-up period.