Introduction and aims: Extramedical use of, and associated harms with pharmaceutical opioids are common. Analysis of coded ambulance clinical records provides a unique opportunity to examine a national population-level indicator of relative harms. This protocol describes an observational study with three aims: (1) to compare supply adjusted rates of pharmaceutical opioid-related ambulance attendances for buprenorphine, codeine, fentanyl, oxycodone, oxycodone-naloxone, morphine, pethidine, tramadol and tapentadol; (2) to compare presentation characteristics for these commonly used pharmaceutical opioids and (3) to describe the context surrounding ambulance presentations related to oxycodone, a widely used opioid with an established abuse liability, and tapentadol, a more recent ‘atypical’ opioid on the Australian market, with fewer studies that have directly examined signals of extramedical use. Method: Trained coders extract data from clinical records for ambulance presentations relating to extramedical use of commonly used pharmaceutical opioids. These data form the basis of a large, national database that captures alcohol-related and drug-related harms. Supply adjusted rates of presentations will be examined using Poisson regression. Multinomial logistic regression will be used to compare severity and other characteristics of attendances relating to different pharmaceutical opioids. Tapentadol-related and oxycodone-related cases will be qualitatively examined to understand the situationally specific contexts of the ambulance attendances outside of the characteristics captured in routinely coded variables. Ethics and dissemination: Ethics approval related to analysis of ambulance attendance data was obtained from the Eastern Health Human Research Ethics Committee (E122 08–09), with an amendment specific to the qualitative analysis. Findings will be submitted for peer review in 2019. The understanding of risk profiles in real-world settings is of international public health importance. The analysis and publication of findings from this national dataset of clinical records will provide one of the most nuanced analyses to date of relative harms across nine pharmaceutical opioids over a 6-year period.