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Abuse potential of extended-release (ER) opioid tablets increases if tampering causes rapid opioid release.To evaluate the susceptibility to tampering of biphasic immediate-release (IR)/ER oxycodone (OC)/acetaminophen (APAP) tablets compared with IR OC/APAP tablets.IR/ER OC/APAP and IR OC/APAP tablets were tested at room temperature and after heating, freezing and microwaving. Resistance to crushing was tested using manual and powered tools (e.g. spoons, mortar and pestle, blender, coffee grinder). Tampered tablets were tested for suitability for snorting, OC extraction in solvents and ease of drawing into a syringe. Dissolution of IR/ER OC/APAP in gastric fluid with and without ethanol was tested to determine the potential for facilitating precipitous release of opioid from the tablet.IR/ER OC/APAP tablets were more crush resistant than IR OC/APAP tablets. Heating, freezing and microwaving had no effect on crush resistance of IR/ER OC/APAP tablets. Although a mortar and pestle pulverized IR/ER OC/APAP tablets, upon contact with solvent, the powder formed a thick gel judged unsuitable for absorption through the nasal mucosa and could not be drawn into a syringe. In contrast, powder from crushed IR OC/APAP tablets dissolved readily, was judged suitable for snorting, and was easily drawn into a syringe. Dissolution of IR/ER OC/APAP tablets in gastric fluid was slowed by the addition of ethanol.IR/ER OC/APAP tablets are resistant to crushing and dissolution compared with IR OC/APAP tablets.IR/ER OC/APAP tablets may have less potential for abuse involving tampering compared with IR OC/APAP tablets.