BACKGROUND AND PURPOSE: Declines in both functional activation and functional connectivity have been reported in patients with sickle cell disease. In this study, we derived the functional and default mode responses to a word stem paradigm in age-, ethnicity-, and background-matched subjects with sickle cell disease and control groups, with the aim of testing whether both networks were similarly attenuated and whether the changes were related to physiologic parameters that characterize sickle cell disease. MATERIALS AND METHODS: Both the functional and default mode responses were obtained from age- and background-matched controls and the sickle cell population by using a visually presented word stem paradigm on a 3T scanner. RESULTS: We observed an attenuated response to both activation and deactivation in the sickle cell disease group. There were no significant differences in the activation response between the 2 groups for the contrast control > sickle cell disease; however, significant differences were observed in the medial parietal cortex, the auditory cortex, and the angular gyrus for the default mode. For the sickle cell group, a significant correlation between the activation z scores and the physiologic parameters was observed; for the deactivation, the results were not significant but the trend was similar. CONCLUSIONS: The results indicate that the physiologic parameters modulate the activation in the expected fashion, but that the effect was weaker for deactivation. Given that significant differences between the 2 groups were only seen for deactivation, additional factors must modulate the deactivation in sickle cell disease.