Background: The metabolic syndrome is related to an increased risk of cardiovascular disease (CVD), as reported by numerous studies. In this analysis, we investigated the relationship between the metabolic syndrome (MetSyn) and CVD risk in hypercholesterolemic patients and the effect of pravastatin treatment in the MEGA Study population. Methods: The MetSyn was defined according to modified National Cholesterol Education Program (NCEP) criteria, namely, the presence of three or more risk factors: 1)obesity (body mass index ≥25 kg/m 2 ), 2)hypertriglyceridemia (≥150 mg/dL), 3)low HDL cholesterol (<40 mg/dL in men and <50 mg/dL in women), 4)hypertension (SBP≥130 mmHg and/or DBP≥85 mmHg), 5)hyperglycemia (fasting glucose ≥100 mg/dL). The risk of CVD and total mortality was compared in patients with and without MetSyn. The effect of pravastatin plus diet therapy in the patients with MetSyn was compared to those without MetSyn, and moreover these comparisons were conducted in two groups, divided according to their LDL cholesterol levels (cut point: 156.9 mg/dL). Results: A total of 2,636 (33.7%) of the 7,832 hypercholesterolemic patients enrolled in MEGA had MetSyn. A 1.9 times higher incidence of CVD was found in the patients with, compared to those without, MetSyn. The risk of CVD in patients with MetSyn was very similar to that in patients with high LDL cholesterol (≥156.9 mg/dL) and with low LDL cholesterol (<156.9 mg/dL). Notably, a 36% significant risk reduction for CVD and 50% risk reduction for total mortality were observed in the patients with MetSyn treated with pravastatin plus diet treatment compared to diet therapy alone. Moreover, the greatest CVD risk reduction was observed in the high LDL-C group with MetSyn compared to those without MetSyn (Hazard ratio 0.44 vs. 0.56, respectively, interaction p=0.07). Conclusion: Metabolic syndrome increases the risk of CVD regardless of the presence or absence of hypercholesterolemia. Diet plus pravastatin treatment is effective for the prevention of CVD for patients with hypercholesterolemia and MetSyn.