Abstract In this pilot study we assessed the efficacy of olanzapine as monotherapy in the treatment of major depressive disorder, without psychosis. We also demonstrated the in vivo 5-HT 2A receptor occupancy of olanzapine using positron emission tomography. An open-label prospective six weeks study design with fourteen patients who met the inclusion and exclusion criteria for the study were enrolled from the general community of the St. Louis metropolitan area. All patients met DSM IV criteria for major depressive disorder without psychosis, had a Hamilton depression rating scale (HAMD 17) score > 18 and were between the ages of 18 and 65. The primary measure of efficacy was the change in HAMD 17 item version total score from baseline to endpoint. The data was collected between 1998 and 2004. There was significant reduction in the HAMD 17 scores from baseline to endpoint. Half the patients ( n = 6) showed ≥ 50% reduction in their HAMD 17 scores. This study points to the potential of olanzapine as a therapeutic agent for the treatment of major depressive disorder without psychosis.