Purpose: The purpose of the study was to determine the effectiveness of megestrol acetate (MA) and olanzapine (OLN) for the treatment of cancer-related anorexia (CRA). Methods: Eighty adult patients with advanced gastrointestinal cancer or lung cancer (stages III and IV) with CRA (loss of appetite and greater than or equal to 5% loss of preillness stable weight) were randomized to receive daily MA or MA plus OLN for a period of 8 weeks. Patients were assessed weekly using the M.D. Anderson Symptom Inventory with specific measurement of weight, appetite, nausea, and quality of life (QOL) measures. Results: For the 37 patients receiving MA, 15 patients had a greater than or equal to 5% weight gain, 2 patients had an appetite improvement, 3 patients had an improvement in nausea, and 5 patients had an improvement in QOL at both 4 and 8 weeks. For the 39 patients receiving MA plus OLN, 33 patients had a greater than or equal to 5% weight gain, 25 patients had an appetite improvement, 21 patients had an improvement in nausea, and 23 patients had an improvement in QOL at both 4 and 8 weeks, and there was an improvement in general activity, mood, work, walking, and enjoyment at 8 weeks. There were no grade III or IV treatment-related toxicities in patients receiving MA or the combination of MA plus OLN. Conclusions: The combination of MA and OLN appears to be an effective intervention for patients with CRA. © Springer-Verlag 2009.