Abstract Background There has been growing interest in the UK and internationally of risk-stratified breast screening whereby individualised risk assessment may inform screening frequency, starting age, screening instrument used, or even decisions not to screen. This study evaluates the cost-effectiveness of eight proposals for risk-stratified screening regimens compared to both the current UK screening programme and no national screening. Methods A person-level microsimulation model was developed to estimate health-related quality of life, cancer survival and NHS costs over the lifetime of the female population eligible for screening in the UK. Results Compared with both the current screening programme and no screening, risk-stratified regimens generated additional costs and QALYs, and had a larger net health benefit. The likelihood of the current screening programme being the optimal scenario was less than 1%. No screening amongst the lowest risk group, and triannual, biennial and annual screening amongst the three higher risk groups was the optimal screening strategy from those evaluated. Conclusions We found that risk-stratified breast cancer screening has the potential to be beneficial for women at the population level, but the net health benefit will depend on the particular risk-based strategy.