Previous fMRI research has found altered brain response after total sleep deprivation (TSD), with TSD effects moderated by task difficulty. Specific models of the impact of sleep deprivation and task difficulty on brain response have yet to be developed. Differences in networks of fMRI measured brain response during verbal encoding in sleep deprived and well-rested individuals were examined with structural equation modeling (SEM). During fMRI scanning, 23 healthy volunteers memorized words either easy or difficult to recall, 12 (well-rested) and 36 hours (sleep deprived) after awaking. A priori models that linked specified regions of interest were evaluated, with the focus on the extent to which two left parietal regions interacted with the left inferior frontal gyrus (Model 1) or with the right inferior frontal gyrus (Model 2). Task difficulty, not TSD, determined which model fit the brain response data; Model 2 fit best for hard words before and after TSD, whereas Model 1 fit best for easy words. TSD altered the patterns of interaction within each of the best fitting models: prefrontal interactions with the left inferior parietal lobe were diminished and intra-parietal interactions increased. Sleep deprivation and item difficulty produce different effects on brain networks involved in verbal learning. (JINS, 2006, 12, 591–597.)