The effects of SB203580 (SB) with different concentrations at different time points on renal function, apoptosis, P38MAPK activity and the expression, as well as the P38MAPK substrates in renal ischemia/reperfusion injury were investigated. Forty-nine rats were divided into 7 groups at random (n = 7 in each group) according to the durations of ischemia/reperfusion injury and the time of medication. Based on the orthogonal Latin side, the rats were injected, by caudal vein, with the same volume but different dosages of SB. BUN and Scr were determined. The apoptosis was detected with TUNEL kit. The protein was assayed qualitatively and semi-quantitatively by Western blot. The results showed that SB could significantly reduce the increased Scr and BUN, the apoptosis of renal tubular epithelia and the activation of P38MAPK all caused by renal ischemia/ reperfusion injury in a dose-dependent manner (P < 0.05). And the effect was most predominant when SB was given 3 h before renal ischemia. This suggested that SB could significantly alleviate renal ischemia/reperfusion injury. Administration of SB 3 h before ischemia at the concentration of 5 micromol/L could obtain an optimal effect.