To determine (a) the proportion of patients at high risk of cardiovascular events who achieve low-density lipoprotein cholesterol (LDL-C) goals as recommended by the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III) guidelines, and (b) the predictors of poor LDL-C control. Two open-label, prospective, non-randomised, observational studies (study 1 with n=19 194 patients, predominantly with coronary artery disease (CHD); study 2 with n=19 484 patients, pre-dominantly with diabetes mellitus (DM)). Patients received, usually after statin pretreatment, ezetimibe 10 mg plus simvastatin as fixed-dose combinations over 3 months. Bivariate and multivariate regression analysis was performed to identify factors associated with poor LDL-C control. At study end, 38% (up from 4.7% at baseline) of CHD and 35% (up from 3.3% at baseline) of diabetic patients achieved the target LDL value <100 mg/dl (2.6 mmol/l) after treatment with a fixed-dose ezetimibe-simvastatin combination. In both studies, concomitant atherosclerotic disease was associated with good control. Conversely, factors associated with poor control were, among others, high baseline LDL-C values, pretreatment with certain statins, and (in the DM study) high HbA(1c), and high body mass index. Under real world, general practice conditions, a substantial proportion of high-risk patients with CHD and/or DM met LDL-C target levels on dual cholesterol inhibition with ezetimibe/simvastatin. A limited number of easily recognisable factors allow physicians to identify high risk patients whose LDL-C is likely to be difficult to control. Early identification of this patient group may have profound clinical benefits in general practice by enabling specific early interventions such as counselling on physical activity, dietary support and/or follow up visits to the GP.