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Opioids and benzodiazepines are frequently used in hospitals, but little is known about outcomes among ward patients receiving these medications.To determine the association between opioid and benzodiazepine administration and clinical deterioration.Observational cohort study.500-bed academic urban tertiary-care hospital.All adults hospitalized on the wards from November 2008 to January 2016 were included. Patients who were “comfort care” status, had tracheostomies, sickle-cell disease, and patients at risk for alcohol withdrawal or seizures were excluded.The primary outcome was the composite of intensive care unit transfer or ward cardiac arrest. Discrete-time survival analysis was used to calculate the odds of this outcome during exposed time periods compared to unexposed time periods with respect to the medications of interest, with adjustment for patient demographics, comorbidities, severity of illness, and pain score.In total, 120,518 admissions from 67,097 patients were included, with 67% of admissions involving opioids, and 21% involving benzodiazepines. After adjustment, each equivalent of 15 mg oral morphine was associated with a 1.9% increase in the odds of the primary outcome within 6 hours (odds ratio [OR], 1.019; 95% confidence interval [CI], 1.013-1.026; P < 0.001), and each 1 mg oral lorazepam equivalent was associated with a 29% increase in the odds of the composite outcome within 6 hours (OR, 1.29; CI, 1.16-1.45; P < 0.001).Among ward patients, opioids were associated with increased risk for clinical deterioration in the 6 hours after administration. Benzodiazepines were associated with even higher risk. These results have implications for ward-monitoring strategies.