BackgroundDrug overdose (OD) deaths in the U.S. continue to rise. After opioids, benzodiazepines (BZD) are the medication most commonly involved in prescription overdoses, yet OD risk factors among those prescribed BZD are not well understood. Our objective was to examine characteristics of BZD, opioid, and other psychotropic prescriptions associated with increased drug OD risk following a BZD prescription.MethodsWe completed a retrospective cohort study using a 20% sample of Medicare beneficiaries with prescription drug coverage. We identified patients with a BZD prescription (“index”) claim between 1 April 2016 and 31 December 2017. In the 6 months pre-index, those without and with BZD claims comprised incident and continuing cohorts, which were split by age (incident < 65 [n= 105,737], 65 + [n= 385,951]; continuing < 65 [n=  240,358], 65 + [n= 508,230]). Exposures of interest were: average daily dose and days prescribed of the index BZD; baseline BZD medication possession ratio (MPR) for the continuing cohort; co-prescribed opioids and psychotropics. Our primary outcome was a treated drug OD event (including accidental, intentional, undetermined, or adverse effect) within 30 days of the index BZD, examined using Cox proportional hazards.ResultsAmong incident and continuing BZD cohorts, 0.78% and 0.56% experienced an OD event. Compared to 14–30 days, a < 14-day fill corresponded to higher OD risk in incident (< 65 adjusted hazard ratio [aHR] 1.16 [95% CI 1.03–1.31]; 65 + : aHR 1.21 [CI 1.13–1.30]) and continuing (< 65: aHR 1.33 [CI 1.15–1.53]; 65 + : aHR 1.43 [CI 1.30–1.57]) cohorts. Among continuing users, lower baseline exposure (i.e., MPR < 0.5) was associated with increased OD risk for those < 65 (aHR 1.20 [CI 1.06–1.36]); 65 + (aHR 1.12 [CI 1.01–1.24]). Along with opioids, concurrent antipsychotic use and antiepileptic use were associated with elevated risk of OD in all 4 cohorts (e.g., aHRs for the continuing 65 + cohort: opioid, 1.73 [CI 1.58–1.90]; antipsychotic, 1.33 [CI 1.18–1.50]; antiepileptic, 1.18 [1.08–1.30]).ConclusionsIn both the incident and continuing cohorts, patients dispensed fewer days' supply were at increased OD risk; those in the continuing cohort with more limited baseline BZD exposure were also at elevated risk. Concurrent medication exposures including opioids, antipsychotics, and antiepileptics were associated with short-term elevated OD risk.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40360-023-00674-x.