A dominant negative H-ras mutant, N116Y, was transfected into a variety of human tumor cell lines. N116Y extremely inhibited the proliferation of A431 (vulva), PC3 (prostate), T24 (bladder), MCF7 (breast), NKPS and TMK1 (stomach) cancer cell lines. A431 and PC3 cells were particularly susceptible to N116Y. In order to examine the effects of N116Y on the neoplastic phenotypes, we transfected a less efficient N116Y expression vector into A431 cells. Almost all clones survived after G418 selection. However, they did not retain the N116Y gene and only one clone faintly expressed N116Y. This N116Y-expressing clone had no tumorigenicity in vivo, and revealed deformed morphology and DNA fragmentation, suggesting that N116Y might have induced apoptotic cell death. Thus, N116Y may be applicable for gene therapy of a wide spectrum of human tumors.