Acute tryptophan depletion (ATD) putatively results in a transient reduction in central serotonin transmission, and induces depressed mood in some un-medicated subjects with remitted major depressive disorder (MDD). The 5-HT transporter promoter region length polymorphism (5-HTTLPR) has been shown to influence behavioral and metabolic responses to ATD, as well as the risk for developing MDD within the context of stress. The current study investigates the relationships between 5-HTTLPR genotype, neurophysiologic response to ATD, and diagnostic phenotype (healthy control subjects versus MDD subjects differentiated by their depressive response to ATD) using 18FDG-PET. Un-medicated subjects with remitted MDD and healthy controls were genotyped for the long (l) and short (s) alleles of the 5-HTTLPR polymorphism and categorized into one of three genotypes. On two separate occasions, subjects received either a placebo or an amino acid mixture designed to deplete plasma tryptophan, followed by 18FDG-PET scanning. Depressive symptoms were rated to determine the diagnostic phenotype. Descriptive and predictive discriminant analyses were performed using brain regional metabolic data to classify according to phenotype and genotype. Overall, 79% of the cases were classified correctly by genotype, and 85% were classified correctly by phenotype. In a leave-one-out cross-validation, 72% of the subjects were classified correctly as carrying an s-allele, and 79% of the subjects were classified correctly by primary diagnosis. The robust nature of the classification results indicates that much of the variance in metabolic response to ATD is accounted for by genotypic and phenotypic category.