In 169 depressed patients randomized to treatment with either fluoxetine or nortriptyline, we examined whether polymorphisms of the serotonin transporter and the G protein β3 subunit influenced response to these antidepressants. For depressed patients under the age of 25 yr the T allele of the G protein β3 subunit was associated with a markedly poorer response to nortriptyline, while serotonin transporter polymorphisms did not predict antidepressant response. However, in patients 25 yr or older, the G protein β3 polymorphisms did not predict antidepressant response, while the s,s genotype of the serotonin transporter was associated with a poorer response to both fluoxetine and nortriptyline. These differential pharmacogenetic predictors of antidepressant response by age, may provide clues to understanding the discontinuities in pharmacological responsiveness of child/adolescent and adult depressive disorders.