Ethyl-eicosapentanoic acid (ethyl-EPA) may be beneficial in the treatment of bipolar disorder (BD) and may have a neurotrophic/neuroprotective role in patients with neuropsychiatric disorders. To investigate this we examined whether ethyl-EPA treatment of BD patients is associated with increased brain levels of N-acetylaspartate (NAA), a putative marker of neuronal integrity. Fourteen female BD outpatients with moderate depressive symptoms were administered 2 g of ethyl-EPA per day or placebo for 12 weeks in a randomized, double-blind fashion. Quantitative, proton magnetic resonance spectroscopy imaging data were obtained prior to randomization and after 12 weeks of treatment from a single 12 ml volume of interest centred above the body of the corpus callosum. A significant rise in NAA levels was observed in the ethyl-EPA treatment group compared with the placebo group (p = 0.027). These results provide the first evidence for a probable neurotrophic role of ethyl-EPA treatment in BD underlining the need for more detailed investigation of its mechanism of action and therapeutic potential.