This study aimed to assess whether exposure to anticholinergic and sedative medications and its evolution was associated with increased risk of in-hospital falls and all-cause mortality. Furthermore, results were compared with 2 definitions of drug burden index (DBI) against the outcomes.This observational, multicentric, and longitudinal study was conducted among patients aged 65 years or older, in 3 geriatric hospitals, in Francheville, Lyon, and Villeurbanne, France (duration of follow-up, 11.6 months). The exposure to anticholinergic and sedative medications was quantified using a DBI, at admission and at the end of observation for 337 patients. The evolution of exposure was the absolute difference between the index at admission and at the end of observation. The outcomes were in-hospital falls and all-cause mortality.Overall, 5.9% of patients experienced a fall. The risk of fall was nearly 3-fold in patients whose DBI increased during hospital stay compared to those with stable or decreased DBI (hazard ratio, 2.9 [1.14-7.12]; P = 0.03), after adjustment for comorbidities.The overall proportion of mortality was 6.5%. The evolution of DBI during hospital stay was not related to the risk of mortality (hazard ratio, 1.9 [0.8-4.4]; P = 0.14). Results were similar with the 2 definitions of DBI.Increased exposure to anticholinergic and sedative medications during hospital stay is associated with a higher risk of in-hospital falls but not with mortality. The DBI could be implemented in hospital, to guide prescription and reduce anticholinergic and sedative drug exposure.