Background: Monoamine oxidase type B inhibitors (iMAO-Bs) are a class of largely-used antiparkinsonian agents that, based on experimental evidence, are supposed to exert different degrees of neuroprotection in Parkinson’s disease (PD). However, clinical proofs on this regard are very scarce. Since cerebrospinal fluid (CSF) reflects pathological changes occurring at brain level, we examined the neurodegeneration-related CSF biomarkers profile of PD patients under chronic treatment with different iMAO-Bs to identify biochemical signatures suggestive for differential neurobiological effects. Methods: Thirty-five PD patients under chronic treatment with different iMAO-Bs in add-on to levodopa were enrolled and grouped in rasagiline (n = 13), selegiline (n = 9), safinamide (n = 13). Respective standard clinical scores for motor and non-motor disturbances, together with CSF biomarkers of neurodegeneration levels (amyloid- \beta -42, amyloid- \beta -40, total and 181-phosphorylated tau, and lactate) were collected and compared among the three iMAO-B groups. Results: No significant clinical differences emerged among the iMAO-B groups. CSF levels of tau proteins and lactate were instead different, resulting higher in patients under selegiline than in those under rasagiline and safinamide. Conclusions: Although preliminary and limited, this study indicates that patients under different iMAO-Bs may present distinct profiles of CSF neurodegeneration-related biomarkers, probably because of the differential neurobiological effects of the drugs. Larger studies are now needed to confirm and extend these initial observations.