We investigated the role of changes in 6 mutually exclusive medication categories on the risk of falling in nursing home residents. The 6 categories were: gastrointestinal, hypoglycemics, antibiotics, central nervous system (CNS) acting, cardiovascular disease agents, and analgesics. A change was defined as a new start, a dose change, an as-needed dose, or a discontinuation. Incident reports were used to determine the fall date and time. Medication records were abstracted to identify the date of changes before the date of each fall. The 158 residents who fell had 419 recorded falls during 2002 and 2003; they were on average 80.5 years old (SD 8.1; range 65-103), and 67% were men. Within 1-3 days of a change in any CNS medication (antipsychotic, sedative, antidepressant, or antiseizure), the fall risk (odds ratio) increased 3.4-fold (95% confidence interval 1.2-9.5) using 7-9 days prior as comparable control days. No changes in other medication categories had a significant effect on fall risk. These data suggest that the risk of falls among nursing home residents is significantly elevated within 3 days of a CNS medication change.