Delirium often causes severe distress for terminally ill cancer patients, and treatment of underlying pathologies is important to achieve symptom alleviation. Although accumulation of morphine metabolites may play an important role in development of delirium, empirical findings are conflicting due to a large inter-individual variation in morphine-related concentrations. To explore intra-individual changes of morphine metabolite concentrations before and after occurrence of terminal delirium, a prospective observational study was performed on terminally ill cancer patients. Among 131 consecutive hospice inpatients, 16 samples from 8 patients who received two blood samplings before and after development of delirium were analyzed. Delirium developed a median of 5 days before death, and clinical causes were attributed to multi-organ failure. Plasma concentrations of morphine-6-glucuronide (M-6-G) and morphine-3-glucuronide (M-3-G) significantly increased after development of delirium within the same patient. Mean normalized concentrations of M-6-G and M-3-G elevated from 1.24 +/- 1.06 to 2.94 +/- 3.52 ng/mL/mg (P = 0.016), and from 7.46 +/- 4.75 to 15.4 +/- 13.2 ng/mL/mg (P = 0.016), respectively. Normalized morphine concentration increased with a marginal statistical significance from 0.54 +/- 0.27 to 0.83 +/- 0.22 ng/mL/mg (P = 0.055). In conclusion, plasma concentrations of M-6-G and M-3-G were significantly higher after development of terminal delirium than before. It is suggested that accumulations of morphine metabolites can contribute to development of delirium in cancer patients whose death is impending.