BACKGROUND: The role of potentially inappropriate medications (PIMs) in mortality has been studied among those 65 years or older. While middle-aged individuals are believed to be less susceptible to the harms of polypharmacy, PIMs have not been as carefully studied in this group. OBJECTIVE: To estimate PIM-associated risk of mortality and evaluate the extent PIMs explain associations between polypharmacy and mortality in middle-aged patients, overall and by sex and race/ethnicity. DESIGN: Observational cohort study. SETTING: Department of Veterans Affairs (VA), the largest integrated healthcare system in the US. PARTICIPANTS: Patients aged 41 to 64 who received a chronic medication (continuous use of ≥ 90 days) between October 1, 2008, and September 30, 2017. MEASUREMENT: Patients were followed for 5 years until death or end of study period (September 30, 2019). Time-updated polypharmacy and hyperpolypharmacy were defined as 5-9 and ≥ 10 chronic medications, respectively. PIMs were identified using the Beers criteria (2015) and were time-updated. Cox models were adjusted for demographic, behavioral, and clinical characteristics. RESULTS: Of 733,728 patients, 676,935 (92.3%) were men, 479,377 (65.3%) were White, and 156,092 (21.3%) were Black. By the end of follow-up, 104,361 (14.2%) patients had polypharmacy, 15,485 (2.1%) had hyperpolypharmacy, and 129,992 (17.7%) were dispensed ≥ 1 PIM. PIMs were independently associated with mortality (HR 1.11, 95% CI 1.04-1.18). PIMs also modestly attenuated risk of mortality associated with polypharmacy (HR 1.07, 95% CI 1.03-1.11 before versus HR 1.05, 95% CI 1.01-1.09 after) and hyperpolypharmacy (HR 1.18, 95% CI 1.09-1.28 before versus HR 1.12, 95% CI 1.03-1.22 after). Patterns varied when stratified by sex and race/ethnicity. LIMITATIONS: The predominantly male VA patient population may not represent the general population. CONCLUSION: PIMs were independently associated with increased mortality, and partially explained polypharmacy-associated mortality in middle-aged people. Other mechanisms of injury from polypharmacy should also be studied.