The blood-oxygenation-level-dependent (BOLD) signal is dependent on multiple physiological factors such as cerebral blood flow (CBF), local oxygen metabolism (CMRO(2)) and cerebral blood volume (CBV). Since caffeine affects both CBF and neural activity, its effects on BOLD remain controversial. The calibrated BOLD approach is an excellent tool to study caffeine because it combines CBF and BOLD measures to estimate changes in CMRO(2). The present study used the calibrated BOLD approach with 5% CO(2) to determine if a 2.5 mg/kg intravenous injection of caffeine changes the coupling between CBF and CMRO(2) during motor and visual tasks. The results show that caffeine decreases n, the CBF:CMRO(2) coupling ratio, from 2.58 to 2.33 in motor (p=0.006) and from 2.45 to 2.23 in visual (p=0.002) areas respectively. The current study also demonstrated that caffeine does not alter cerebrovascular reactivity to CO(2). These results highlight the importance of the calibrated BOLD approach in improving interpretation of the BOLD signal in the presence of substances like caffeine.