Reduced serotonin (5-HT) function and abnormalities in the hypothalamic-pituitary-adrenal (HPA) axis are thought to play a role in the aetiology of major depression. We sought to examine this issue in the elderly by assessing the effects of lowering brain 5-HT on salivary and plasma cortisol in elderly patients who had recovered from at least one episode of major depression and in a healthy, age matched comparison group. A double-blind, cross-over design involving administration of two nutritionally balanced amino acid mixtures (with or without tryptophan) was used. Salivary cortisol was measured at intervals before and after the drink. There was no effect of acute tryptophan depletion (ATD) on salivary cortisol (ATD by time; F=0.97, df=7,210, p=0.454) but a significant interaction between group and time (F=3.91, df=7,210, p=0.010). Healthy subjects showed a marked increase in cortisol levels 2-3 hours into the procedure regardless of drink composition while recovered depressed subjects did not. In elderly patients who had recovered from depression there was no evidence of greater vulnerability of hypothalamic 5-HT pathways to 5-HT depletion. However, they demonstrated reduced reactivity of the HPA axis compared to healthy subjects.