Background: Plasma Neurofilament light chain (pNfL) is a promising biomarker to discriminate Frontotemporal dementia (FTD) from other diagnoses such as Alzheimer’s disease (AD) or psychiatric disorders. Currently, the diagnostic criteria for FTD syndromes are structured hierarchically into “Possible”, “Probable” and “Definite” levels depending on the degree of confidence set by biomarkers. We aim to study the diagnostic and prognostic values of pNfL in the different confidence levels of FTD diagnosis.Method: Patients fulfilling criteria for FTD were classified as “Possible”, “Probable” or “Definite” FTD based on the current diagnostic criteria. pNfL levels were determined with SiMoA, and then compared to Control and AD groups, as well as within the different levels of confidence in the FTD diagnosis.Result: 187 subjects were included: 37 controls, 79 AD and 71 FTD (11 Possible, 49 Probable and 11 Definite). The FTD group showed higher concentrations of pNfL than the Control (p < 0.001, AUC: 0.817) and the AD groups (p < 0.001, AUC: 0.677) (Figure 1A and 1B).Within the FTD group, pNfL levels differed across the different diagnostic confidence levels (Figure 1C). Subjects with Probable and Definite FTD showed higher levels of pNfL than subjects with Possible FTD (p < 0.001 and p < 0.01 respectively). By contrast, the Possible FTD group did not show differences in pNfL concentrations with the control group. In that sense, the diagnostic value of pNfL varied according to the different grades of diagnostic confidence (Figure 1D), with cases with probable or definite FTD exhibiting an excellent AUC to distinguish from controls (AUC 0.860 and 0.908 respectively), but with no discrimination between possible FTD and controls (AUC 0.583).pNfL presented an excellent performance in the differentiation of structural or functional impairment in the neuroimage (AUC 0.94, and AUC 0.86 respectively) (Figure 2). Finally, higher baseline pNfL levels were associated with worse clinical progression in FTD cases (Figure 3).Conclusion: pNfL were higher in FTD patients compared to controls or AD patients. However, we found significant variation across the different confidence levels of FTD diagnosis. Finally, pNfL predicted neuroimage alterations and a worse clinical progression in FTD patients.