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BACKGROUND/OBJECTIVES: Green tea is being recognized as a beverage with potential benefits for human health and cognitive functions. In vivo studies provide preliminary evidence that green tea intake may have a positive role in improving effects on cognitive functions. We aimed to examine the neural effects of green tea extract on brain activation in humans. SUBJECTS/METHODS: Functional magnetic resonance imaging was recorded while 12 healthy volunteers performed a working memory task following administration of 250 or 500 ml of a milk whey based green tea containing soft drink or milk whey based soft drink without green tea as control in a double-blind, controlled repeated measures within-subject design with counterbalanced order of substance administration. A whole-brain analysis with a cluster-level threshold of Po0.001 (unadjusted) was followed by an a priori-defined region of interest (ROI) analysis of the dorsolateral prefrontal cortex (DLPFC) including a cluster-level threshold of Po0.05 and family-wise error (FWE) adjustment for multiple comparisons. RESULTS: Whole-brain analyses revealed no significant effects after correction for multiple comparisons (FWE Po0.05). Using a ROI approach, green tea extract increased activation in the DLPFC relative to a control condition (FWE Po0.001). This neural effect was related to green tea dosage. Green tea extract was not associated with any significant attenuation in regional activation relative to control condition. CONCLUSIONS: These data suggest that green tea extract may modulate brain activity in the DLPFC, a key area that mediates working memory processing in the human brain. Moreover, this is the first neuroimaging study implicating that functional neuroimaging methods provide a means of examining how green tea extract acts on the brain.