The serotonin 5-HT1A receptor system is implicated in the pathophysiology of major depressive disorder (MDD) (Stockmeier, 2003) and serotonergic medications are currently widely used in the treatment of MDD. Previous molecular imaging studies in patients with MDD have provided evidence of a widespread decrease in the density of serotonin 5-HT1A receptors in the disease (Drevets et al. 1999; Sargent et al. 2000 ; Bhagwagar et al. 2004 ; Meltzer et al. 2004 ; Hirvonen et al. 2008, but see Parsey et al. 2006 for opposite results). Psychotherapy usually results in clinically identical outcomes with medication in the treatment of patients with mild to moderate MDD (Ebmeier et al. 2006). However, nothing is known about the molecular mechanisms mediating the effects of psychotherapy. To test and compare the effects of fluoxetine medication and a brief psychotherapy on 5-HT1A receptor density in patients with MDD we conducted a randomized comparative study. Positron emission tomography (PET) scanning with the 5-HT1A radiotracer [carbonyl-C]WAY-100635 was performed before and after the intervention to measure alterations in 5-HT1A receptor binding.