Measures of the spatial extent of functional activation are important for a number of functional magnetic resonance imaging (fMRI) applications, such as pre-surgical planning and longitudinal tracking of changes in brain activation with disease progression and drug treatment. The interpretation of the data from these applications can be complicated by inter-subject or inter-session variability in the measured fMRI signals. Prior studies have shown that modulation of baseline cerebral blood flow (CBF) can directly alter the functional CBF and blood oxygenation level dependent (BOLD) responses, suggesting that the spatial extents of functional activation maps based on these signals may also depend on baseline CBF. In this study, we used a caffeine dose (200 mg) to decrease baseline CBF and found significant (p<0.05) reductions in both the CBF activation extent and contrast-to-noise ratio (CNR) but no significant changes in the BOLD activation extent and CNR. In contrast, caffeine significantly changed the temporal dynamics of the BOLD response but not the CBF response. The decreases in the CBF activation extent and CNR were consistent with a significant caffeine-induced decrease in the absolute CBF change accompanied by no significant change in the residual noise. Measures of baseline CBF also accounted for a significant portion of the inter-subject variability in the CBF activation map area and CNR. Factors that can modulate baseline CBF, such as age, medication, and disease, should therefore be carefully considered in the interpretation of studies that use functional CBF activation maps.