To describe the prevalence of unplanned hospitalizations caused by adverse drug reactions (ADRs) in older veterans and to examine the association between this outcome and polypharmacy after controlling for comorbidities and other patient characteristics.

Retrospective cohort.

Veterans Affairs Medical Centers.

Six hundred seventy‐eight randomly selected unplanned hospitalizations of older (aged ≥ 65) veterans between October 1, 2003, and September 30, 2006.

Naranjo ADR algorithm, ADR preventability, and polypharmacy (0–4, 5–8, and ≥9 scheduled medications).

Seventy ADRs involving 113 drugs were found in 68 (10%) hospitalizations of older veterans, of which 25 (36.8%) were preventable. Extrapolating to the population of more than 2.4 million older veterans receiving care during the study period, 8,000 hospitalizations may have been unnecessary. The most common ADRs that occurred were bradycardia (n = 6; beta‐blockers, digoxin), hypoglycemia (n = 6; sulfonylureas, insulin), falls (n = 6; antidepressants, angiotensin‐converting enzyme inhibitors), and mental status changes (n = 6; anticonvulsants, benzodiazepines). Overall, 44.8% of veterans took nine or more outpatient medications and 35.4% took five to eight. Using multivariable logistic regression and controlling for demographic, health‐status, and access‐to‐care variables, polypharmacy (≥9 and 5–8) was associated with greater risk of ADR‐related hospitalization (adjusted odds ratio (AOR) = 3.90, 95% confidence interval (CI) = 1.43–10.61 and AOR = 2.85, 95% CI = 1.03–7.85, respectively).

ADRs, determined using a validated causality algorithm, are a common cause of unplanned hospitalization in older veterans, are frequently preventable, and are associated with polypharmacy.