The effects of caffeine on BOLD responses are still controversial. The potential explanation to this discrepancy may be associated with different dietary caffeine consumption among subjects. Here, we test the effect of caffeine on BOLD responses by using the caffeine-naïve animals. By reducing the baseline cerebral blood flow and therefore increasing the baseline deoxygenation concentration, caffeine significantly enhanced the magnitude of BOLD responses to the electrical whisker pad stimulation. These findings may suggest that caffeine-naïve animals could be a potential model to shed more light on effects of caffeine on BOLD fMRI measurements.