As our understanding of the underlying defects in fragile X syndrome (FXS) increases so does the potential for development of treatments aimed at modulating the defects and ameliorating the constellation of symptoms seen in patients. Symptoms of FXS include cognitive disability, hyperactivity, autistic behaviour, seizures and learning deficits. Lithium is a drug used clinically to treat bipolar disorder, and it has been used to treat mood dysregulation in individuals with FXS. We examined whether dietary lithium would alter behavioural and morphological abnormalities in fmr1 knockout (KO) mice. We studied wild-type (WT) and KO mice untreated (control chow) or treated with lithium (0.3% lithium-carbonate-containing chow) commenced at weaning and maintained throughout the experiment. At age 8-12 wk, mice were subjected to the following behavioural tests: open field, social interaction, elevated plus maze, elevated zero maze and passive avoidance. At 13 wk, brains were prepared for Golgi staining and analysis of dendritic spine morphology in medial prefrontal cortex. We found that compared to untreated WT, untreated KO mice were hyperactive and had reduced anxiety, impaired social interactions, and deficits on a learning test. Dendritic spines in medial prefrontal cortex were longer and increased in number. Lithium treatment ameliorated the hyperactivity and reversed impaired social interaction and deficits on the learning test. Lithium treatment also partially normalized general anxiety levels and dendritic spine morphology. Our findings and those from other laboratories on the efficacy of lithium treatment in animal models support further studies in patients with FXS.