Objective To explore the effect of temozolomide on apoptosis and molecular mechanism in small cell lung cancer (SCLC) cell H446. Methods The effect of temozolomide on the viability of H446 cell was measured by MTT assay.The effect of temozolomide on cell cycle was detected by flow cytometry.The activation of phosphatidyl inositol 3-kinase (PI3K)/AKT signaling pathway and expression level of downstream target genes (Cyclin B1), cell division cycle 2 (Cdc2), Bax, Bcl-2 and Survivin were detected by western blot.Results Temozolomide (50, 100, 200 μmol/L) could inhibit H446 cell viability, and the inhibitory rate was highest at 48 h.Moreover, temozolomide made H446 cell cycle arrested in G2 phase.Western blott showed the expression of PI3K, Cyclin B1, Cdc2, Bcl-2, Survivin and the phosphorylation of AKT were reduced, but the expression of Bax were increased by temozolomide.Conclusion Temozolomide could induce SCLC cell H446 apoptosis via blocking PI3K/AKT signal pathway.