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Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (
C9orf72)
have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at
TMEM106B
influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that
TMEM106B
is a genetic modifier of FTLD-TDP caused by progranulin (
GRN
) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with
C9orf72
expansions (
n
= 14), with the major allele correlated with later age at death (
p
= 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with
C9orf72
expansions (
n
= 75), again finding that the major allele associates with later age at death (
p
= 0.016), as well as later age at onset (
p
= 0.019). In contrast,
TMEM106B
genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for
GRN
mutations or
C9orf72
expansions. Thus,
TMEM106B
is a genetic modifier of FTLD with
C9orf72
expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in
C9orf72
expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.