AIMS: To test if polysubstance use profiles and drug-related outcomes differ between those receiving and not receiving opioid substitution therapies (OST), among people who inject drugs (PWID). DESIGN: An annual cross-sectional, sentinel sample of PWID across Australia SETTING: Data came from three years (2011-2013) of the Illicit Drug Reporting System (IDRS). PARTICIPANTS: A total of 2,673 participants who injected drugs from the combined national IDRS samples of 2011 (n = 868), 2012 (n = 922), and 2013 (n = 883) MEASUREMENTS: Latent Class Analysis (LCA) was used to summarise participants' self-reported use of 18 types of substances, with the resulting polysubstance use profiles then associated with participant experience of a number of drug-related outcomes. FINDINGS: Polysubstance use profiles exhibiting a broad-range of substance use were generally at increased risk of negative drug-related outcomes whether participants were receiving OST or not: including thrombosis among OST receivers [odds ratio (OR)=2.13, 95% confidence intervals (CI) = 1.09-4.17], injecting with used needle among OST receivers and non-receivers respectively [OR = 2.78, 95% CI = 1.50-5.13; OR = 2.15, 95% CI = 1.34-3.45], and violent criminal offences among OST receivers and non-receivers respectively [OR = 2.30, 95% CI = 1.16-4.58; OR = 1.87, 95% CI = 1.14-3.07]. An important exception was non-fatal overdose which was specifically related to a class of PWID who were not receiving OST and used morphine frequently [OR = 1.83, 95% CI = 1.06-3.17]. CONCLUSION: Regardless of opioid substitution therapies usage, people who inject drugs (PWID) who use a broad-range of substances experience greater levels of injecting-related injuries and poorer health outcomes and are more likely to engage in criminal activity than other groups of PWID.