A functional polymorphism in the serotonin transporter gene (5-HTTLPR) has been reported to modulate amygdala responsiveness to negative environmental cues. However, it remains unclear whether 5-HTTLPR modulates amygdala responses specifically to negative stimuli or rather to emotionally salient stimuli in general. In 44 healthy subjects, amygdala responses to subliminally presented happy and sad facial expressions were assessed by means of fMRI at 3 Tesla. All subjects were genotyped for 5-HTTLPR and the recently discovered 5-HTT rs25531. We observed a robust emotion by genotype group interaction in the right amygdala. Risk allele carriers (S or LG) showed similar amygdala responses to happy faces compared to homozygous LALA carriers but increased amygdala responses to sad faces. The right amygdala was the only anatomical region across the whole brain demonstrating this interaction at a reasonable threshold. It appears that whereas 5-HTT gene variation modulates automatic amygdala responsiveness to sad faces, no such association was found for happy faces. We conclude that 5-HTTLPR genotype predominantly impacts the central processing predominantly of negative environmental cues but not of emotionally salient stimuli in general.