Background We previously reported that patients with early-stage bipolar disorder, but not healthy comparison controls, had body mass index (BMI)-related volume reductions in limbic brain areas, suggesting that the structural brain changes characteristic of bipolar disorder were more pronounced with increased weight. Aims To determine whether the most consistently reported neurochemical abnormality in bipolar disorder, increased glutamate/glutamine (Glx), was also more prominent with higher BMI. Method We used single-voxel proton magnetic resonance spectroscopy to measure hippocampal Glx in 51 patients with first-episode mania (mean BMI = 24.1) and 28 healthy controls (mean BMI = 23.3). Results In patients, but not healthy controls, linear regression demonstrated that higher BMI predicted greater Glx. Factorial ANCOVA showed a significant BMI6diagnosis interaction, confirming a distinct effect of weight on Glx in patients. Conclusions Together with our volumetric studies, these results suggest that higher BMI is associated with more pronounced structural and neurochemical limbic brain changes in bipolar disorder, even in early-stage patients with low obesity rates.