BACKGROUND: Cognitive impairment is a common and persistent feature of depression, yet it remains poorly understood and inadequately treated. Preclinical and human studies suggest that stimulating 5-HT4 receptors (5-HT4R) enhances neuroplasticity and improves cognition. This novel study examines the cognitive effects of 5-HT4R agonism in adults with a history of recurrent depression. METHODS: Fifty participants who were not currently depressed but had experienced at least two previous episodes of depression were randomized in a double-blind design either to prucalopride (2 mg daily, titrated from 1 mg) or to placebo for 7-10 days. Participants completed self-report questionnaires and a task battery at baseline and post-intervention assessing declarative memory, working memory, emotional processing, and executive function. RESULTS: Compared to placebo, prucalopride significantly improved word recall on an auditory verbal learning task and was associated with faster response times on a complex working memory task without loss of accuracy. It also improved the accurate recognition of rapidly presented facial expressions. Composite analysis of non-emotional tasks identified that the prucalopride group participants post-intervention were faster and more accurate than at baseline compared to those receiving placebo. Prucalopride had minimal effects on affective cognition, consistent with previous findings. Cognitive improvements were independent of baseline mood symptoms or self-reported cognitive difficulties. CONCLUSIONS: Short-term 5-HT4R agonism improved performance on multiple objective cognitive measures in individuals with remitted depression. These findings replicate our previous results in healthy volunteers showing a pro-cognitive effect of prucalopride and support a role for 5-HT4Rs as a promising target for cognitive enhancement in mood disorders.