Biological vulnerability for bipolar disorders (BD) in relatives of BD patients has not as yet been established. Serotonergic vulnerability was studied, using acute tryptophan depletion (ATD), in healthy first-degree relatives of BD patients and healthy controls. The effects of ATD on mood and cortisol release in 30 healthy adult, lifetime symptom free, unaffected first-degree relatives of BD patients (Family History; FH) were compared with effects in 15 healthy matched controls in a placebo-controlled, double-blind, crossover design. During ATD and placebo, salivary cortisol response was also assessed during a stress-inducing speech task (SIST). First-degree relatives of type II BD patients (FH II) showed an elevation of mood, whereas control subjects and relatives of type I BD patients (FH I) showed a lowering of mood after ATD. ATD was followed by a decrease in cortisol level in both FH subgroups, but not in the controls. The results suggest serotonergic vulnerability that affected mood in FH II subjects and cortisol release in both FH I and FH II subjects.