In a previous analysis using a lung cancer cell lines model, we have found that therapies directed against sCLU and its downstream signaling targets pAkt and pERK1/2 may have the potential to enhance the efficacy of cisplatin (DDP)-based chemotherapy in vitro. Here, we investigated the therapies directed against sCLU on the DDP-based chemotherapy in vivo, and explored the mechanism. Using lung cancer cell lines, A549 cells and DDP-resistant A549 cells (A549DDP), we determined the effect of sCLU silencing using short interfering double-stranded RNA (siRNA) on chemosensitivity in immunocompromised mice bearing A549DDP tumors. We then determined the effect of sCLU overexpression via stable sCLU transfection on chemosensitivity in immunocompromised mice bearing A549 tumors. The effect of sCLU silencing or overexpression on pAkt and pERK1/2 expression and chemosensitivity in vivo was detected by western blot assay. The results showed sCLU silencing increased the chemosensitivity of A549DDP cells to DDP in vivo via downregulation of pAkt and pERK1/2 expression. And sCLU overexpression decreased the chemosensitivity of A549 cells to DDP in vivo via upregulation of pAkt and pERK1/2 expression. DDP-induced sCLU activation, which involved induction of pAkt and pERK1/2 activation that confer DDP resistance in immunocompromised mice. Alteration of this balance allows sensitisation to the antitumor activity of cisplatin chemotherapy.