The effectiveness of rosuvastatin in improving lipid measurements and achieving guideline target levels in patients has been demonstrated in short-term randomised clinical trials. The Framingham Heart Study has provided some of the strongest evidence in establishing the relationship between risk factors such as smoking, hypertension and cholesterol and events from cardiovascular disease and subsequent mortality. Using Framingham risk equations for coronary heart disease, we used a Markov model to extrapolate beyond short-term trial evidence to calculate the cost-effectiveness of cholesterol-lowering therapy in 55-year-old men and women, with an initial total cholesterol: high-density lipoprotein cholesterol (TC:HDL) ratio of 5.5 and an untreated expected survival (under adjusted Framingham risk equations) of 17 years (men) and 19 years (women). After titration, cholesterol-lowering therapy reduced the weighted average TC:HDL ratio to 3.4 (rosuvastatin), 3.7 (atorvastatin), 3.9 (simvastatin), 4.1 (fluvastatin) and 4.2 (pravastatin). In comparison with no treatment, rosuvastatin produced the greatest health gain (0.71 quality-adjusted life-years [QALYS]) and pravastatin the smallest (0.42). In the base case analysis, rosuvastatin dominated atorvastatin and delivered additional benefits at the cost of £9,735 per QALY for men in comparison with generic simvastatin. Sensitivity analysis showed a high probability of rosuvastatin being cost-effective under conditions of uncertainty.