Opioid-related mortality continues to rise. Though risks of prescription opioid misuse and abuse are well known, short-term mortality across a range of prescription opioid exposure is unclear. This study was conducted in order to assess the short-term mortality associated with quantity of reported opioid prescriptions, DESIGN: An observational analysis was performed using data from the Medical Expenditure Panel Survey, years 2005-2015, a population-based, nationally representative household survey. This study included adults (age 18+) with prescription data and death status reported during their 2-year survey participation. Key exposure is the number of opioid prescriptions (0, 1-5, 6 or more) in year 1 of survey participation. The main outcome is all-cause mortality reported during the 2-year survey participation. Of 90,622 participants, 14% reported at least 1 opioid prescription. There were 774 (0.9%) deaths during the survey period, 551 (0.7%) among those not reporting opioids, 127 (1.2%) among those reporting 1-5 opioid prescriptions, and 96 (3.9%) among those reporting 6 or more opioid prescriptions. After adjusting for sociodemographics, health status, and utilization, there was no significant association between category of opioid prescriptions and death during the study period; adjusted odds ratios = 0.86 (95% CI = 0.66, 1.22, p = 0.27) and 0.99 (95% CI = 0.74, 1.34, p = 0.96), respectively, for 1-5 prescriptions and 6 or more prescriptions. In a nationally representative sample, opioid prescriptions were associated with increased short-term mortality only without adjustment for sociodemographics, health status, or utilization. The relationship between prescription opioid use and mortality risk is more complex than previously reported, meriting further examination.