OBJECTIVES: To determine whether current use of central nervous system (CNS)-active medications, including benzodiazepines, antidepressants, anticonvulsants, and narcotics, increases the risk for subsequent falls. DESIGN: Prospective cohort study. SETTING: Four clinical centers in Baltimore, Maryland; Portland, Oregon; Minneapolis, Minnesota; and the Monongahela Valley, Pennsylvania. PARTICIPANTS: Eight thousand one hundred twenty-seven women aged 65 and older participating in the fourth examination of the Study of Osteoporotic Fractures between 1992 and 1994. MEASUREMENTS: Current use of CNS-active medications was assessed with an interviewer-administered questionnaire with verification of use from medication containers. A computerized dictionary was used to categorize type of medication from product brand and generic names. Incident falls were reported every 4 months for 1 year after the fourth examination. RESULTS: During an average follow-up of 12 months, 2,241 women (28%) reported falling at least once, including 917 women (11%) who experienced two or more (frequent) falls. Compared with nonusers, women using benzodiazepines (multivariate odds ratio (MOR) = 1.51, 95% confidence interval (CI) = 1.14-2.01), those taking antidepressants (MOR = 1.54, 95% CI = 1.14-2.07), and those using anticonvulsants (MOR = 2.56, 95% CI = 1.49-4.41) were at increased risk of experiencing frequent falls during the subsequent year. We found no evidence of an independent association between narcotic use and falls (MOR = 0.99 for frequent falling, 95% CI = 0.68-1.43). Among benzodiazepine users, both women using short-acting benzodiazepines (MOR = 1.42, 95% CI = 0.98-2.04) and those using long-acting benzodiazepines (MOR = 1.56, 95% CI = 1.00-2.43) appeared to be at greater risk of frequent falls than nonusers, although the CIs overlapped 1.0. We found no evidence to suggest that women using selective serotonin-reuptake inhibitors (MOR = 3.45, 95% CI = 1.89-6.30) had a lower risk of frequent falls than those using tricyclic antidepressants (MOR 1.28, 95% CI = 0.90-1.84). CONCLUSIONS: Community-dwelling older women taking CNS-active medications, including those taking benzodiazepines, antidepressants, and anticonvulsants, are at increased risk of frequent falls. Minimizing use of these CNS-active medications may decrease risk of future falls. Our results suggest that fall risk in women taking benzodiazepines is at best marginally decreased by use of short-acting preparations. Similarly, our findings indicate that preferential use of selective serotonin-reuptake inhibitors is unlikely to reduce fall risk in older women taking antidepressants.