ABSTRACT Background Women with Down syndrome have a lower breast cancer risk and significantly lower life expectancies than women without Down syndrome. Therefore, it is not clear whether mammography screening strategies used for women without Down syndrome would benefit women with Down syndrome in the same way. Objective To determine the benefits and harms of various mammography screening strategies for women with Down syndrome using collaborative simulation modeling. Design Two established Cancer Intervention and Surveillance Modeling Network (CISNET) simulation models estimated the benefits and harms of various screening strategies for women with Down syndrome over a lifetime horizon. Participants We modeled a hypothetical cohort of US women with Down syndrome who were born in 1970. Interventions Annual, biennial, triennial, and one-time digital mammography screenings during the ages 40–74. Main Measures The models estimated numbers of mammograms, false-positives, benign biopsies, breast cancer deaths prevented, and life-years gained per 1000 screened women when compared with no screening. Key Results In average-risk women 50–74, biennial screening incurred 122 mammograms, 10 false-positive mammograms, and 1.4 benign biopsies per one life-year gained compared with no screening. In women with Down syndrome, the same screening strategy incurred 2752 mammograms, 242 false-positive mammograms, and 34 benign biopsies per one life-year gained compared with no screening. The harm/benefit ratio varied for other screening strategies, and was most favorable for one-time screening at age 50, which incurred 1629 mammograms, 144 false-positive mammograms, and 20 benign biopsies per one life-year gained compared with no screening. Conclusions The harm/benefit ratios for various mammography screening strategies in women with Down syndrome are not as favorable as those for average-risk women. The benefit of screening mammography for women with Down syndrome is less pronounced due to lower breast cancer risk and shorter life expectancy.