Medication use patterns provide popular surrogate measures of disease, yet selective under-use of drugs by elderly patients with potentially unmeasured comorbidity may lead to artifactual "protective" associations between use of specific drugs and mortality. We examined the relation between use of 20 common classes of drugs and mortality among the 129,111 residents of New Jersey 65-99 years of age who had at least one hospitalization during the years 1991-1994 and filled prescriptions through either Medicaid or that state's Pharmacy Assistance for the Aged and Disabled program. Each study drug class was used by more than 5,000 subjects during the 120 days before hospitalization; 41,930 subjects died in the hospital or during the year after discharge. Users of drugs from each of seven therapeutic classes had reduced age- and sex-adjusted rates of death relative to non-users: lipid-lowering agents, nonsteroidal anti-inflammatory agents, beta blockers, thiazides, glaucoma drugs, calcium channel blockers, and anti-anxiety drugs. Adjustment for comorbidity and polypharmacy had little effect on these results. We found similar results in a separate nonhospitalized cohort of 132,071 elderly persons. Much of this observed association appears to be nonetiologic. These findings raise concerns about using observational studies in high-risk populations to infer associations between drug use and outcomes.