As a neurotransmitter, serotonin (5-HT) is widely used throughout the brain and known to play a role in many processes including emotion and brain development. Of the 15 subtypes of 5-HT receptors, the 1A receptor (5-HT(1A)) has been implicated in depression and suicide. Using the [carbonyl-(11)C]WAY100635 ([(11)C]WAY) ligand and positron emission tomography, we have studied the 5-HT(1A) receptor, first in a group of healthy controls, then in two separate groups of subjects with major depressive disorder (MDD) (antidepressant exposed and not recently medicated), and, lastly, in a group of subjects remitted from MDD. All MDD subjects were medication-free at the time of scan. We found higher 5-HT(1A) binding potential (BP(F)) in MDD subjects not recently exposed to an antidepressant compared with controls and recently medicated MDD subjects; and higher BP(F) in subjects with the C(-1019)G promoter polymorphism. We replicated these findings in a novel cohort and reconciled our discrepant findings with other groups using alternate quantification techniques. We also reported higher BP(F) in subjects remitted from a major depressive episode than in controls. From this work, we proposed a temporal model in which 5-HT(1A) BP(F) may be a trait abnormality of MDD. To further explore the genetic components of MDD and utility of 5-HT(1A) imaging as a potential tool for biomarker or treatment response prediction, these findings should be replicated in a larger cohort using the [(11)C]CUMI-101 agonist tracer.