Polypharmacy has previously been found to increase and exercise interventions to reduce the risk of falls and fall-related injuries. In this study, women who had four or more regular medications benefitted the most from the exercise intervention and had the lowest fall risk compared to the reference group. Fall injuries among older people cause significant health problems with high societal costs. Previously, some exercise interventions have been found to reduce the number of falls and related injuries. We studied how different levels of medication use affect the outcome of an exercise intervention in terms of preventing falls. This exercise RCT involved 914 women born in 1932-1945 and randomly assigned to the intervention (n = 457) and control (n = 457) groups. Both groups participated in functional tests three times during the study. Baseline self-reported prescription drug use was trichotomized: 0-1, 2-3, and ≥ 4 drugs/day (i.e. polypharmacy group). We used Poisson regression for follow-up fall risk and Kaplan-Meier survival analysis for fractures. During follow-up, 1380 falls were reported, 739 (53.6%) resulting in an injury and pain and 63 (4.6%) in a fracture. Women with polypharmacy in the intervention group had the lowest fall risk (IRR 0.713, 95% CI 0.586-0.866, p = 0.001) compared to the reference group that used 0-1 medications and did not receive the intervention. Overall, the number of medications associated with the fall incidence was only seen in the intervention group. However, the number of medications was not associated with fractures in either of the groups. Weaker functional test results were associated with polypharmacy in the control group. The most prominent decrease in fall risk with exercise intervention was seen among women with polypharmacy. Targeting these women might enhance fall prevention efficacy among the aging population.Trial Registration: The study has been registered in ClinicalTrials.gov. Trial registration number NCT02665169. Register date 27/01/2016.