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Gastric cancer (GC) remains one of the leading causes of cancer-associated mortality. The overexpression of inhibitor of apoptosis-stimulating protein of p53 (iASPP) has been detected in GC tissues but the function of iASPP in the viability of GC cells and its underlying molecular mechanism remains unknown. Kruppel-like factor 4 (KLF4) is a tumor suppressor gene in GC and it may interact with p53. iASPP is an evolutionarily conserved inhibitor of p53, whereas KLF4 may be negatively associated with iASPP in GC. However, whether KLF4 has regulatory effects on iASPP remains to be investigated. The objective of the present study was to examine the function of iASPP and KLF4 in the proliferation of GC cells and to determine whether KLF4 has regulatory effects on iASPP. It was demonstrated that iASPP was upregulated and KLF4 was downregulated in GC cell lines. Downregulation of iASPP inhibited the proliferation and colony formation ability, and promoted the apoptosis of GC cells. Additionally, upregulation of KLF4 inhibited the proliferation and colony formation ability, and promoted apoptosis of GC cells. Furthermore, upregulation of KLF4 inhibited the expression of iASPP. Upregulation of iASPP following overexpression of KLF4 reversed the KLF4-mediated effects in GC cells. In vivo upregulation of KLF4 or downregulation of iASPP inhibited the growth of tumors, whereas upregulation of iASPP promoted the growth of tumors. In conclusion, iASPP may act as an oncogene that promotes the proliferation of GC cells. The results demonstrated that KLF4 was a negative regulatory factor of iASPP and that overexpression of iASPP inhibited the effects of KLF4. Thus, downregulation of KLF4 in GC may lead to overexpression of iASPP and promote the development of cancer. [ABSTRACT FROM AUTHOR]