Background: Most volumetric magnetic resonance imaging (MRI) studies of the hippocampus in patients with bipolar disorder (BD) show no differences in hippocampal volume between patients and healthy controls. Significant variability, however, exists in the medication status of patients included in these studies. Lithium appears to have neuroprotectve effects and may influence hippocampal volume. Objective: To determine whether lithium therapy exerts a long-term effect on hippocampal volume and to determine whether there is evidence of biochemical change in the hippocampus of patients with long term BD. Methods: We examined the effects of lithium on hippocampal volumes over a period of 2 to 4 years in patients with BD who had never received pharmacotherapy before lithium initiation. Using a GE Signa, 3-Tesla scanner, we also performed proton magnetic resonance spectroscopy to examine levels of N-acetyl aspartate, glutamate and choline-containing compounds in the hippocampus of patients with established BD. RESULTS: We found bilateral increases in volume of the hippocampus over time. We also found that choline-containing compounds were significantly increased in the hippocampi of patients with a long history of illness. Conclusion: Consistent with preclinical literature supporting the neuroprotective effects of lithium, long-term treatment is associated with increased hippocampal size in vivo. We have preliminary evidence that this may be associated with improvement in recollective memory function. Whether lithium can minimize or reverse some of the biochemical changes that appear to be associated with BD remains to be confirmed.