In mammography screening programmes, women are screened according to a one-size-fits-all principle. Tailored screening, based on risk levels, may lead to a better balance of benefits and harms. With microsimulation modelling, we determined optimal mammography screening strategies for women at lower (relative risk [RR] 0.75) and higher (RR 1.8) than average risk of breast cancer, eligible for screening, using the incremental cost-effectiveness ratio (ICER) of current uniform screening in the Netherlands (biennial [B] 50-74) as a threshold ICER. Strategies varied by interval (annual [A], biennial, triennial [T]) and age range. The number of life-years gained (LYG), breast cancer deaths averted, overdiagnosed cases, false-positive mammograms, ICERs and harm-benefit ratios were calculated. Optimal risk-based screening scenarios, below the threshold ICER of €8883/LYG, were T50-71 (€7840/LYG) for low-risk and B40-74 (€6062/LYG) for high-risk women. T50-71 screening in low-risk women resulted in a 33% reduction in false-positive findings, a similar reduction in costs and improved harm-benefit ratios compared to the current screening schedule. B40-74 in high-risk women led to an increase in screening benefit, compared to current B50-74 screening, but a relatively higher increase in false-positive findings. In conclusion, optimal screening consisted of a longer interval and lower stopping age than current uniform screening for low-risk women, and a lower starting age for high-risk women. Extending the interval for women at lower risk from biennial to triennial screening reduced harms and costs while maintaining most of the screening benefit., (© 2020 UICC.)