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A growing body of evidence indicates extracellular signal-regulated kinase (ERK1/2) participates in various stress-induced responses which isconsider to beinvolved in pathophysiology of depression. Surprisingly, the effect of antidepressants on ERKs is almost unexplored, particularly from the perspective of sexes.In the present study, we investigated the potential role of cytoplasm-nuclear distribution of phospho-ERK1/2 in the hippocampus of chronically stressed female and male Wistar rats and if those potential changes could be attenuated with chronic fluoxetine treatment. In females, stress induced cytosolic retention of phospho-ERKs, while in malesitpromoted the nuclear translocation of phospho-ERK 1/2. The effect of concomitant fluoxetine treatment was more pronounced in stressed females, with main focus on normalization of its nuclear phospho-ERK 1/2 levels.