Patients with multiple sclerosis (MS) demonstrate worse cognition on warmer days. Here, we examine the neurophysiology underlying this temperature-cognition relationship. The association between task-related BOLD fMRI activation and outdoor temperature was investigated in 28 MS patients who demonstrated worse cognitive function on warmer days. In MS patients, warmer outdoor temperature was associated with greater BOLD activation during performance of a simple sustained attention task. The brain areas that showed greater activation on warmer days (p = .01) were regions that have been shown to be more activated by MS patients during task performance: frontal, dorsolateral prefrontal, and parietal cortex. The relationship between outdoor temperature and cerebral activation was absent in healthy controls. The purpose of this study was to identify the neurophysiological basis for worse cognition among MS patients on warmer days. We show here that MS patients activate task-related brain regions more on warmer days. Increased brain activation required by MS patients on warmer days to perform a simple task may signify neural inefficiency.