Objectives of study are around investigation the effect of the central nervous system stimulant modafinil on brain striatum neurodegeneration caused by subcutaneous (s.c.) rotenone administration in rats, further, the possible modulation by modafinil on L-dopa effect on oxidative stress, inflammation and nigrostriatal cell damage. Seven groups of Male albino mice received dimethyl sulfoxides.c., rotenone (1.5 mg/kg, s.c., 3 times per week), rotenone/L-dopa (25 mg/kg, p.o., daily), rotenone/modafinil (0.1, 0.2 and 0.3 mg/kg respectively, p.o., daily), rotenone/L-dopa/modafinil (0.2 mg/kg, p.o. daily). The treatment was continued for 2 weeks. Mice were tested for behavioral changes 24h after the end of treatments.Mice were evaluated for brain biochemical markers of oxidative stress (lipid peroxidation, reduced glutathione, and nitric oxide), pro-inflammatory factors (tumor necrosis factor-α, interlukin-1beta) and dopamine level. Histopathologic examination and the expression of the anti-apoptotic protein caspase-3 were also performed. Rotenone significantly elevated oxidative stress and pro-inflammation, decreased dopamine, induced substantianigra damage with caspase-3-mediated apoptosis respectly to the control levels. Results of modafinil or its combination with L-dopa may have potential therapeutic effect in Parkinson's disease by decreasing pro-inflammation and oxidative stress, increasing dopamine, preventing the development of neuronal damage and reducing caspase-3 expression in the striatum.