Objective To observe the changes of phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) in the medial prefrontal cortex (mPFC) of chronic forced swimming rats. Methods Thirty male Wistar rats were randomly divided into two groups with fifteen in each. The chronic forced swimming stress (CFSS) model animals were given swimming stress for 15min once daily for 28 days, and the controls were free of stress. The depression behavior was examined using sucrose preference test, openfiled test and Morris water maze. The expression of pERK1/2 was detected using immunohistochemistry and Western blotting. Results The consumption of sucrose and preference of sucrose in CFSS group were (4.114±0.644)%, (86.610±4.450)% respectively, those in control group were (8.157±1.105)%, (94.930±2.893)% (EM>P/EM><0.01). The erect quantity in CFSS group and control group were 1.75±0.96, 6.00±0.82 respectively (P<0.05), and the escape latency in two group were (20.762±3.236)s, (5.632±1.065)s (EM>P/EM><0.01). The result of immunohistochemistry analysis showed that the integral absorbance of pERK1/2positive cells in control group and CFSS group were 47.594±5.355 and 110.810±10.643 respectively (EM>P/EM><0.01). Western blotting showed that relative expression