The major aim of this study was to evaluate the efficiency of chitosan microspheres containing cyclosporine-A (Cs-A) on mitochondrial damage in traumatic brain injury (TBI) animal model. Trauma was introduced to male Sprague-Dawley (SD) rats similar to that of modified Feeney Method. Briefly, after craniectomy in the left parietal region (5 mm). Trauma was performed by dropping 24 g metal sterile rods through a teflon guide tube (9.3 cm) on a foot plate placed over the duramater. Just after the trauma, 20 mg/kg Cs-A (Sandimmune (R) has been administered to the traumatised SD rats intraperitoneally (i.p.). On the other hand, only chitosan microspheres containing 10 mg/kg was implanted at the craniectomy area locally after trauma in Group E. A small piece of surgicell was placed over the craniectomy hole and the scalp incision was sutured. 24 h after injury and the brain tissues were removed intact. The results were evaluated through lipid peroxidation ratio and ultrastructural grading system. The statistical comparisons were evaluated by using Mann Whitney U test at the significance level p = 0.05. The lipid peroxidation ratios of sham (78.4 +/- 6.0 nmol/g tissue) and vehicle (80.2 +/- 10.6 nmol/g tissue) were significantly increased 24 h after TBI. However, for treatment groups (i.p. Cs-A; 20 mg/kg) and (10 mg/kg Cs-A in microspheres), statistically significant lower lipid peroxidation ratios were determined as 53.5 +/- 9.7 and 47.9 +/- 8.1 nmol/g tissue, respectively (p < 0.05). The mitochondrial damage scores of the treatment groups were recorded as 21.7 +/- 2.6 and 19.4 +/- 3.9 for Group D and Group E, respectively. Both of these scores of the treatment groups were found as significantly different from the sham and vehicle groups' scores individually. The implantation of microsphere formulation has provided a better efficiency in keeping the uniformity of mitochondrial structure in this complex cascade of events after TBI.