Objective The aims were to determine: (i) quantity and frequency of same-day use of opioids with benzodiazepines and/or alcohol amongst people who regularly tamper with pharmaceutical opioids; and (ii) socio-demographic, mental health, harms and treatment profile associated with same-day use of high doses. Method The cohort (n = 437) completed a retrospective 7-day diary detailing opioid, benzodiazepine, and alcohol intake. Oral morphine equivalent (OME) units and diazepam equivalent units (DEU) were calculated, with >200 mg OME, >40 mg DEU and >4 standard alcoholic drinks (each 10 g alcohol) considered a "high dose". Results One-half (47%) exclusively consumed opioids without benzodiazepines/alcohol; 26% had days of opioid use with and without benzodiazepines/alcohol; and 26% always used opioids and benzodiazepines/alcohol. Same-day use of opioids with benzodiazepines/alcohol typically occurred on 1-3 days in the past week. Six in ten (61%) participants reported high dose opioid use on at least one day; one in five (20%) reported high dose opioid and high dose benzodiazepine/alcohol use on at least one day. The latter group were more likely to use prescribed opioid substitution therapy, often alongside diverted pharmaceutical opioids. Socio-demographic and clinical profiles did not vary according to high dose opioid, alcohol and benzodiazepine use, and there was no association with harms. Conclusions Same-day use of opioids with benzodiazepines/alcohol, and high dose combinations, are common amongst people who tamper with pharmaceutical opioids. Assessment of concomitant benzodiazepine/alcohol use during opioid therapy, implementation of real-time prescription monitoring systems, and research to clarify upper safe limits for polydrug depressant use, are potential implications.