In cancer patients, cognitive impairment, psychological distress, and anxiety may accompany and aggravate pain. Neuroleptics are frequently used to control these symptoms and may be used to treat pain that has been unresponsive to more conventional approaches. Because of prominent side effects of traditional neuroleptics and conflicting data regarding their analgesic efficacy, their use in the treatment of pain remains controversial. Olanzapine, an atypical neuroleptic, might offer advantages because of its safer side effect profile. It has also been shown to have an independent antinociceptive activity in animals. The use of olanzapine in the management of cancer pain has not been previously described. We prospectively collected the data on 8 cancer patients with severe pain, uncontrolled in spite of aggressive opioid titration, who received olanzapine to treat severe anxiety and mild cognitive impairment. Patients did not meet criteria for delirium and their cognitive impairment was defined as cognitive disorder not otherwise specified (NOS) according to DSM-IV. Patients received 2.5 to 7.5 mg of olanzapine daily. In all patients, opioid requirements had escalated rapidly prior to starting olanzapine. Levels of pain, sedation, and opioid use were measured 2 days before and 2 days after olanzapine was started. Cognitive state was assessed daily. All 8 patients had marked reduction of the daily pain scores. The average daily opioid use decreased significantly in all patients. Cognitive impairment and anxiety resolved within 24 hours of initiating olanzapine. In these 8 patients, decreased pain scores and opioid requirements may have resulted from improvement in cognitive function and the known anxiolytic effect of olanzapine. Other mechanisms may include independent or adjuvant analgesic effects of olanzapine. We conclude that olanzapine may be useful in the treatment of patients with uncontrolled cancer pain associated with cognitive impairment or anxiety. Further studies to evaluate possible analgesic effect of olanzapine are needed.