OBJECTIVES: To quantify the major determinants of population cost effectiveness of clinical guidelines for risk screening and prevention of cardiovascular disease (CVD) with 'statin' therapy. METHODS: Risk profiles were collected for 4704 men age 35-84y and 1216 women age 45-84y without CVD. 5-year risk of a cardiovascular hospital admission for each individual was calculated using a Framingham risk equation. The predicted number of incident events in 5 years was scaled by age and gender to the 2001 NZ census population and integrated over age groups. Costs, benefits and cost effectiveness were estimated at treatment thresholds Tc/HDLc=4.0 to 6.5 and 5y risk 10% or 15%; and screening age thresholds 35/45 (M/F) to 50/60y and treatment adherence 50% to 84%. RESULTS: In the NZ population of 784K men age 35-84y and 558K women age 45-84y, at treatment thresholds of Tc/HDLc=5.5 and 15% 5y risk, 56K men and 20K women would be eligible for prophylaxis. Compared to no intervention, 5y prophylaxis with 84% adherence would avert 3875 incident cardiovascular events and add 3712 life years at an incremental cost of $NZ29M and ICER < $NZ8000 ($US4000) per event avoided or LYG (discounted at 5%). The ICERs change 2 to 3-fold with treatment adherence (50% vs 84%), threshold lipid ratio (4.5 or 6.5 vs 5.5) and threshold screening age (50/60 vs 35/45) but less than 25% with treatment efficacy (24% vs 30%) and the 5y risk treatment threshold (10% vs 15%). The cost per LYG also depends strongly on the 5y cardiovascular fatality rate and the discount rate. CONCLUSIONS: Prophylaxis with 'statins' is very cost effective at current drug prices and clinically realistic treatment thresholds. Clinical guidelines for cardiovascular prophylaxis should focus on the threshold age for risk screening, the threshold lipid ratio and methods for enhancing treatment adherence.