Currently there is no treatment to reverse the progression of established disability in patients with multiple sclerosis (MS). Therefore, in the present study the therapeutic efficacy of allogeneic mesenchymal stem cells (MSCs) and MSCs-derived neural progenitor cells (MSCs-derived NPs) in chronic experimental autoimmune encephalomyelitis (EAE) has been investigated. The results showed that administration of both MSCs and MSCs-derived NPs decreased significantly the clinical scores of EAE compared to untreated EAE group (1.6±0.17, 1.1±0.29 and 2.4±0.26, respectively; p=0.001). Interestingly, IFN-γ and IL-17 levels in the culture supernatant of MOG35-55-specific splenocytes showed a significant decrease in EAE mice treated with MSCs or MSCs-derived NPs compared to control EAE mice (for IFN-γ: 325 ± 154 pg/mL and 200 ± 15 pg/mL versus 1600 ± 31 pg/mL, respectively; p= 0.009; for IL-17: 28 ± 4.2 pg/mL and 27 ± 5.6 pg/mL versus 108 ± 5.6 pg/mL, respectively; p=0.01). In addition, in comparison to EAE control mice, the levels of IL-10 were significantly higher in the supernatant of MOG35-55-stimulated splenocytes derived from MSCs or MSCs-derived NPs-treated mice (31.5 ± 1.3 pg/mL versus 76 ± 9.8 pg/mL or 75 ± 7.4 pg/mL, respectively; p=0.05 or p=0.03, respectively). However, proliferation of MOG35-55-specific splenocytes was only significantly decreased in MSCs-derived NPs treated group compared to un-treated controls (11000 ± 2872 CPM and 13162 ± 2332 CPM, respectively; p=0.001). In addition, MSCs-derived NPs produced significantly more PGE2 in the culture supernatant compared to MSCs after 24h (6313±239 pg/ml and 5316±328 pg/ml, respectively; p= 0.05) or 48h (6519 ± 49 pg/ml and 5828±229; respectively; p=0.05) of culture. Therefore, allogenic MSCs-derived NPs can be considered as a new promising approach for the therapy of established disability in MS patients.