There is a need for biomarkers allowing early and differential diagnosis between frontotemporal lobar degeneration (FTLD) and other dementias. Notable candidates include routine Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers (pTau181P, hTau, Aβ1-42), non-phosphorylated tau fraction (pTau rel), neurofilament light chain (NF-light), phosphorylated neurofilament heavy chain (pNF-H), progranulin and cathepsin D. Using a cohort of definite FTLD patients, we aimed to explore the performance of these CSF biomarkers. Definite FTLD patients (n=45), clinically diagnosed AD patients (n=45), definite Creutzfeldt-Jakob disease (CJD) patients (n=20) and cognitively healthy controls (n=20) were included in this study. FTLD-TDP (n=28, including 10 GRN and 17 C9orf72 mutation carriers), FTLD-tau (n=10) and FTLD-other (n=7) subgroups were defined by genetic carrier status and/or postmortem neuropathological confirmation. CSF biomarker levels were quantified using commercially available ELISA kits for pTau181P, hTau and Aβ1-42 (INNOTEST ELISAs, Fujirebio Europe, Belgium); hTAU total and pTAU rel (AJ Roboscreen, IBL International GmbH, Germany); NF-light (UmanDiagnostics, IBL International GmbH, Germany); pNF-H (EnCor Biotechnology Inc., USA); progranulin (Adipogen Inc., Korea); cathepsin D (Calbiochem, Merck KGaA, Germany). CSF progranulin levels were significantly lower in FTLD-TDP patients as compared to the FTLD-tau subgroup, due to low levels in GRN mutation carriers. To differentiate between FTLD and AD, pTau181P was the best single marker (AUC=0.922). For further differentiation between FTLD and AD patients, a decision tree was constructed, which showed an added value for NF-light and total tau, correctly classifying 90.8% of the patients (Figure 1). Differentiation between FTLD and controls still proves difficult, with NF-light being the best single marker (AUC=0.700). A decision tree showed that besides NF-light, Aβ1-42 could aid as well, correctly classifying 80.6% of the subjects. The easiest differentiation was that between FTLD and CJD with pTau rel as the best single marker (AUC=0.999). pNF-H and cathepsin D did not contribute to (differential) diagnosis of FTLD. Using single markers, pTau181P and hTau together with NF-light can correctly classify up to 90.8% of FTLD and AD dementia patients. Differentiation between FTLD and controls remains suboptimal, even when combining NF-light and Aβ1-42 (correct classification of 80.6%). Decision tree for differential diagnosis between FTLD and AD patients, with an overall correct classification of 90.8%. pTau181P, phosphorylated tau; hTau, total tau; NF-light, neurofilament light chain.