Summary Background Despite the prognostic value of metabolic syndrome for predicting cardiovascular events, few trials have investigated the effects of statin therapy on cardiovascular morbidity and mortality in patients with the metabolic syndrome. Our post hoc analysis of the Treating to New Targets (TNT) study assessed whether intensive lowering of low-density lipoprotein cholesterol with high-dose atorvastatin therapy results in cardiovascular benefits for patients with both coronary heart disease and the metabolic syndrome. Methods The TNT study was a prospective, double blind, parallel-group trial done at 256 sites in 14 countries between April, 1998, and August, 2004, with a median follow-up of 4·9 years. 10 001 patients were enrolled aged 35–75 years with clinically evident coronary heart disease. Our analysis includes 5584 patients with metabolic syndrome based on the 2005 NCEP ATP III criteria. Patients were randomly assigned to receive either atorvastatin 10 mg per day (n=2820) or 80 mg per day (n=2764). The primary outcome measure was time to first major cardiovascular event, defined as death from coronary heart disease, non-fatal non-procedure-related myocardial infarction, resuscitated cardiac arrest, or fatal or non-fatal stroke. Findings In patients with coronary heart disease and metabolic syndrome, mean on-treatment low-density lipoprotein cholesterol concentrations at 3 months were 2·6 mmol/L (99·3 mg/dL) with atorvastatin 10 mg, and 1·9 mmol/L (72·6 mg/dL) with atorvastatin 80 mg. At a median follow-up of 4·9 years, major cardiovascular events occurred in 367 (13%) patients receiving atorvastatin 10 mg, compared with 262 (9·5%) receiving atorvastatin 80 mg (hazard ratio 0·71; 95% CI 0·61–0·84; p<0·0001). Irrespective of treatment assignment, significantly more patients with metabolic syndrome (11·3%) had a major cardiovascular event at a median of 4·9 years than those without metabolic syndrome (8·0%; hazard ratio 1·44; 95% CI 1·26–1·64; p<0·0001). This increased risk was significantly reduced by intensive therapy with atorvastatin 80 mg beyond that achieved with atorvastatin 10 mg. Interpretation These data indicate that patients with coronary heart disease and metabolic syndrome derive incremental benefit from high-dose atorvastatin therapy, irrespective of the presence of diabetes.