OBJECTIVES: To assess the effect of generics and reference prices for simvastatin, lovastatin and pravastatin, introduced since 2003, on the cost-efficacy of statins in Spain. METHODS: The effect was assessed determing the cost-efficacy of atorvastatin 10-80 mg/day, simvastatin and pravastatin 10-40 mg/day and lovastatin and fluvastatin 20-80 mg/day  in terms of annual treatment costs per percentage of LDL-cholesterol reduction in 2003 and 2008. Annual treatment costs included medication, control measures and adverse side affects. Efficacy of statins to reduce LDL-cholesterol was determined developing a meta-analysis including long-term clinical trials published between 1993 and 2005. Average and incremental cost-efficacy ratios were calculated to assess the efficiency of statin therapies and to develop recommendations for cholesterol-lowering therapies based on cost-efficacy. RESULTS: Efficacy of statin therapies in terms of percentage of LDL-cholesterol reduction ranged from 19 % for pravastatin 10 mg/day to 54 % for atorvastatin 80 mg/day. In 2008, cost-efficacy ratios in terms of cost per % of LDL-cholesterol reduced were €8-10 for simvastatin, €11-14 for lovastatin, €11-37 for atorvastatin, €14-23 for fluvastatin and €18-31 for pravastatin. Cost-efficacy ratios decreased between 2003 and 2008 by 4-7 % for atorvastatin, 33-51 % for simvastatin (p<0.05), 24-38 % for lovastatin (p<0.05), 4-5 % for fluvastatin and 16-23 % for pravastatin (p<0.05). Based on cost-efficacy in 2008, atorvastatin 20-80 mg/day should be the first election therapy in patients requiring a LDL-cholesterol reduction of >41 %, simvastatin 40 mg/day or atorvastatin 10 mg/day in those requiring a reduction of 35-41 % and simvastatin 10-20 mg/day in those requiring a reduction <35 %. CONCLUSIONS: Generics and reference prices have driven down statins’ prices between 2003 and 2008, increasing the cost-efficacy of all statins. Atorvastatin should be the first election drug in patients requiring a high LDL-cholesterol reduction and simvastatin in patients requiring a LDL-cholesterol reduction of less than 35 %.