Rationale Low-dose acute tryptophan depletion (LD-ATD), while having no effect on mood, has been shown to reduce specificity of autobiographical memory in patients who have recovered from a depressive episode. Objectives This study aimed to explore if reduced specificity of autobiographical memory with LD-ATD is common to other groups of individuals at risk of depression, specifically a healthy population with a family history of depression. Methods Nineteen healthy young adults with at least one first-degree relative with a history of major depression were recruited. LD-ATD drinks containing 1.15 g of tryptophan (T+) or no tryptophan (T-) were administered on two separate occasions, in a double blind random order crossover design. The Autobiographical Memory Test (AMT) was administered 5 h after drink administration. Results Analysis of variance revealed a significant difference in the effects of LD-ATD drinks on plasma free tryptophan with no mood change with either drink. There was no within-subject main effect of LD-ATD on the memory task. However, there was a main effect of order of drink. Exploratory analysis of visit 1 data indicated a large between-subject effect (d01.4) of LD-ATD on AMT with T- associated with less specificity in response to negative cue words (F(1, 17)08.71, p=0.009). Conclusions Similar to findings following recovery from depression, LD-ATD can reduce specificity of AMT in the absence of lowered mood in healthy individuals with a strong family history of depression. These findings may reflect a 5-HT-dependent cognitive vulnerability to depression in different populations and warrant further research.