Abstract Background Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 ( C9ORF72 ) are causative for frontotemporal dementia (FTD) and motor neuron disease (MND). Substantial phenotypic heterogeneity has been described in patients with these expansions. We set out to identify genetic modifiers of disease risk, age at onset, and survival after onset that may contribute to this clinical variability. Results We examined a cohort of 330 C9ORF72 expansion carriers and 374 controls. In these individuals, we assessed variants previously implicated in FTD and/or MND; 36 variants were included in our analysis. After adjustment for multiple testing, our analysis revealed three variants significantly associated with age at onset (rs7018487 [ UBAP1 ; p-value = 0.003], rs6052771 [ PRNP ; p-value = 0.003], and rs7403881 [ MT-Ie ; p-value = 0.003]), and six variants significantly associated with survival after onset (rs5848 [ GRN ; p-value = 0.001], rs7403881 [ MT-Ie ; p-value = 0.001], rs13268953 [ ELP3 ; p-value = 0.003], the epsilon 4 allele [ APOE ; p-value = 0.004], rs12608932 [ UNC13A ; p-value = 0.003], and rs1800435 [ ALAD ; p-value = 0.003]). Conclusions Variants identified through this study were previously reported to be involved in FTD and/or MND, but we are the first to describe their effects as potential disease modifiers in the presence of a clear pathogenic .