Background and Objective: Cognitive reserve (CR) mediates the clinical expression of brain pathology in Alzheimer’s disease, while there are much less relevant data in frontotemporal dementia (FTD). In the present study we examined whether CR, measured using the Cognitive Reserve Index (CRI), correlated with regional cerebral blood flow (rCBF) in Greek FTD patients. Methods: Eighty FTD patients, i.e., 47 with behavioral variant FTD (bvFTD) and 33 with primary progressive aphasia (PPA), were enrolled into this study. CR was assessed using the CRI questionnaire, which provides a total score (CRI) and 3 subscores, i.e., CRI-education, CRI-working activity, and CRI-leisure time. The FTD-Clinical Dementia Rating Scale was used to assess the severity of dementia and a brain SPECT study was performed to measure rCBF. Finally, multiple regression analyses were conducted to explore correlations between CR indices and frontotemporal rCBF. Results: In both the bvFTD and the PPA groups, higher scores in the CRI, CRI-education, and CRI-leisure time correlated with lower rCBF in the bilateral frontal and left temporal cortex, respectively, controlling for age, sex, time since symptom onset, and disease severity. Conclusion: In the present study, lifetime participation in leisure time activities was found to mitigate the burden of disease in bvFTD and PPA patients. Moreover, FTD patients with a higher educational attainment were able to cope better with greater brain damage. Determination of the most suitable activities to build an adequate level of CR is crucial for dementia prevention.