Introduction: Pathophysiology of depression is a controversial issue. Hippocampal lesions could lead into depression as well as to changing the levels of several cytokines, including brain-derived neurotrophic factor (BDNF) and tumor necrosis factor alpha (TNF- α). The present study was aimed to investigate the mechanism of depression induced by trimethyltin (TMT) intoxication and to study the effect chronic administration of lithium chloride (Li) on depression in this animal model. Materials and Methods: The animals were divided into TMT+Li20, TMT+Li40, TMT+ Li80 and TMT+Salin groups, which were received 8 mg/kg TMT and 20, 40 or 80 mg/kg of Li or saline, respectively, for fourteen days. In order to define the depression level, the immobility time of the rats was measured in the forced swim test (FST), and tail suspension test (TST). Then, the serum level of TNF-α, BDNF and wet weight of the brains were measured. Results: The immobility time in FST and TST was longer in the rats who received TMT, whereas the rats receiving Li showed a significantly less immobility compared to the TMT+Saline group. In addition, Li administration increased the serum level of BDNF and wet weight of the brains and decreased the TNF-α level compared to the TMT+Saline group. Conclusion: The decrease in BDNF or the increase in inflammation factors (especially TNF-α) occurred in accompany by depression symptoms in TMT intoxication model. On the other hand, chronic administration of Li may modulate the cytokines and amelioration of behavioral symptoms.