ABSTRACT Medical treatments, including drugs, surgical interventions, and vaccinations, play a crucial role in the prevention and treatment of chronic and infectious disease in older adults. Studies providing the evidence base for the benefits and harms of these treatments include both experimental studies (randomized controlled trials, RCTs) and nonexperimental studies (observational, epidemiologic, or, more recently: real-world evidence). Nonexperimental studies provide critically important evidence for older adults, especially those with multiple chronic conditions with polypharmacy, as such adults are rarely included in RCTs; this is doubly important for racially marginalized older adults that are historically underrepresented in trials. Such nonexperimental studies often involve confounding, and many confounders in older adults-including frailty-can be difficult to capture in real-world data. Failure to adjust for this confounding can distort findings and lead to suboptimal or even harmful treatment decisions (if nonexperimental studies are the only evidence available) or the conduct of costly RCTs of treatments without benefits. Timely assessment of treatment benefit and harm in older adults in real-world (versus experimental) settings requires development, refinement, and application of methods to reduce confounding bias in nonexperimental studies. We have addressed this topic since 2005 with funding from R01/R56 AG023178 and AG056479. This effort has led to substantial advances in methods to improve the validity of nonexperimental research applying propensity score methods. Using both empirical data and extensive simulations, we have developed novel analytic techniques to reduce confounding, including propensity score calibration and the exclusion of patients treated contrary to prediction. We have disseminated our results in the form of oral presentations, posters, and workshops/symposia and 112 peer-reviewed publications, including 23 in top epidemiologic journals (AJE and Epidemiology), 23 in the top pharmacoepidemiologic journal (PDS), 10 in Medical Care, and several in top medical journals (JAMA, JNCI, Diabetes Care, and JAGS). Building on our work over the last 15 years to increase the validity of nonexperimental methods to assess the preventive effects of treatments in older adults, we propose significant and innovative aims that improve the rigor of nonexperimental research. We will address these aims using motivating examples from empirical data and extensive simulations to improve the validity of real-world evidence. We will take advantage of our interdisciplinary expertise and access to Medicare data linked with other data sources to improve real-world studies using propensity scores. This proposal is timely: linked data are becoming more available and the role of real-world evidence in regulatory decision making is a central discussion point. This work will directly inform clinically relevant treatment decisions, provide re...