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INTRODUCTION: Alzheimer's disease (AD) correlates with the dysfunction of metabolic pathways that translates into neurological symptoms. An arginine deficiency, a precursor of nitric oxide (NO), has been reported for AD patients. We aimed to evaluate the effect of citrulline oral supplementation on cognitive decline in an AD murine model. METHODS: Three-month citrulline or water supplementation was blindly given to male and female wild type and 3xTg-AD mice trained and tested in the Morris Water Maze (MWM). Cerebrospinal fluid and brain tissue were collected. Ultra Performance Liquid Chromatography was used for arginine determinations while the Griess method was used for NO.RESULTS: Eight-month-old male 3xTg-AD mice supplemented with citrulline performed significantly better in the MWM task; arginine levels increased in cerebrospinal fluid although no changes were seen in brain tissue and only a tendency of increase of NO was observed. DISCUSSION: Citrulline oral administration is a viable treatment for memory improvement in the early stages of AD pointing to NO as a viable, efficient target for memory dysfunction in AD.