Cross-tolerance among opioid analgesics may be a barrier to effective pain management. Although the exact mechanism is unknown, methadone continues to remain a viable option when other opioids have failed. Limited data are available regarding the impact of high-dose methadone on subsequent opioid analgesics. Conventional opioid doses may be insufficient for an analgesic effect in patients previously treated with methadone. A case of profound morphine tolerance following high-dose methadone therapy is described. The potential role of methadone-induced cross-tolerance is discussed.