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Abstract Objective To identify clinicopathological differences between frontotemporal lobar degeneration (FTLD) due to mutations in progranulin (FTLD‐GRN) and chromosome 9 open reading frame 72 (FTLD‐C9ORF72). Methods We performed quantitative neuropathologic comparison of 17 FTLD‐C9ORF72 and 15 FTLD‐GRN with a focus on microglia. For clinical comparisons, only cases with high quality medical documentation and concurring diagnoses by at least two neurologists were included (14 FTLD‐GRN and 13 FTLD‐C9ORF72). Neuropathological analyses were limited to TDP‐43 Type A to assure consistent assessment between the groups, acknowledging that Type A is a minority of C9ORF72 patients. Furthermore, only cases with sufficient tissue from all regions were studied (11 FTLD‐GRN and 11 FTLD‐C9ORF72). FTLD cases were also compared to age– and sex–matched normal controls. Immunohistochemistry was performed for pTDP‐43, IBA‐1, CD68, and GFAP. Morphological characterization of microglia was performed in sections of cortex blinded to clinical and genetic information. Results FTLD‐GRN patients had frequent asymmetric clinical features, including aphasia and apraxia, as well as more asymmetric cortical atrophy. Neuropathologically, FTLD‐C9ORF72 had greater hippocampal tau pathology and more TDP‐43 neuronal cytoplasmic inclusions. FTLD‐GRN had more neocortical microvacuolation, as well as more IBA‐1–positive ameboid microglia in superficial cortical layers and in subcortical white matter. FTLD‐GRN also had more microglia with nuclear condensation, possibly indicating apoptosis. Microglial morphology with CD68 immunohistochemistry in FTLD‐GRN and FTLD‐C9ORF72 differed from controls. Interpretation Our findings underscore differences in microglial response in FTLD‐C9ORF72 and FTLD‐GRN as shown by significant differences in ameboid microglia in gray and white matter. These results suggest the differential contribution of microglial dysfunction in FTLD‐GRN and FTLD‐C9ORF72 and suggest that clinical, neuroimaging and pathologic differences could in part be related to differences in microglia response.