The World Health Organization (WHO) guidelines for the treatment of cancer pain recommend nonopioid analgesics as first-line therapy, so-called "weak" analgesics combined with nonopioid analgesics as second-line therapy, and so-called "strong" opioids (with nonopioid analgesics) only as third-line therapy. However, these guidelines can be questioned with regard to the extent of efficacy as well as the rationale for not using strong opioids as first-line treatment, especially in terminal cancer patients. The purpose of this randomized study was to prospectively compare the efficacy and tolerability of strong opioids as first-line agents with the recommendations of the WHO in terminal cancer patients. One hundred patients with mild-moderate pain were randomized to treatment according to WHO guidelines or to treatment with strong opioids. Evaluated outcomes included pain intensity, need for change in therapy, quality of life, Karnofsky Performance Status, general condition of the patient, and adverse events. No between-treatment differences were observed for changes in quality of life or performance status, but patients started on strong opioids had significantly better pain relief than patients treated according to WHO guidelines (P=0.041). Additionally, patients started on strong opioids required significantly fewer changes in therapy, had greater reduction in pain when a change was initiated, and reported greater satisfaction with treatment than the comparator group (P=0.041). Strong opioids were safe and well-tolerated, with no development of tolerance or serious adverse events. These data suggest the utility of strong opioids for first-line treatment of pain in patients with terminal cancer.