OBJECTIVES: To evaluate the relationship between inappropriate prescribing, medication underuse, and the total number of medications used by patients. DESIGN: Cross-sectional study. SETTING: Veterans Affairs Medical Center. PARTICIPANTS: One hundred ninety-six outpatients aged 65 and older who were taking five or more medications. MEASUREMENTS: Inappropriate prescribing was assessed using a combination of the Beers drugs-to-avoid criteria (2003 update) and subscales of the Medication Appropriateness Index that assess whether a drug is ineffective, not indicated, or unnecessary duplication of therapy. Underuse was assessed using the Assessment of Underutilization of Medications instrument. All vitamins and minerals, topical and herbal medications, and medications taken as needed were excluded from the analyses. RESULTS: Mean age was 74.6, and patients used a mean+/-standard deviation of 8.1+/-2.5 medications (range 5-17). Use of one or more inappropriate medications was documented in 128 patients (65%), including 73 (37%) taking a medication in violation of the Beers drugs-to-avoid criteria and 112 (57%) taking a medication that was ineffective, not indicated, or duplicative. Medication underuse was observed in 125 patients (64%). Together, inappropriate use and underuse were simultaneously present in 82 patients (42%), whereas 25 (13%) had neither inappropriate use nor underuse. When assessed by the total number of medications taken, the frequency of inappropriate medication use rose sharply from a mean of 0.4 inappropriate medications in patients taking five to six drugs, to 1.1 inappropriate medications in patients taking seven to nine drugs, to 1.9 inappropriate medications in patients taking 10 or more drugs (P<.001). In contrast, the frequency of underuse averaged 1.0 underused medications per patient and did not vary with the total number of medications taken (P=.26). Overall, patients using fewer than eight medications were more likely to be missing a potentially beneficial drug than to be taking a medication considered inappropriate. CONCLUSION: Inappropriate medication use and underuse were common in older people taking five or more medications, with both simultaneously present in more than 40% of patients. Inappropriate medication use is most frequent in patients taking many medications, but underuse is also common and merits attention regardless of the total number of medications taken.