Human lateral prefrontal cortex (LPFC) is thought to play a critical role in enabling cognitive flexibility, particularly when performing novel tasks. However, it remains to be established whether LPFC representation of task-relevant information in such situations actually contributes to successful performance. We utilized pattern classification analyses of functional MRI activity to identify novelty-sensitive brain regions as participants rapidly switched between performance of 64 complex tasks, 60 of which were novel. In three of these novelty-sensitive regions—located within distinct areas of left anterior LPFC—trial-evoked activity patterns discriminated correct from error trials. Further, these regions also contained information regarding the task-relevant decision rule, but only for successfully performed trials. This suggests that left anterior LPFC may be particularly important for representing task information that contributes to the cognitive flexibility needed to perform successfully in novel task situations.