Abstract Background Both mutational inactivation of the adenomatous polyposis coli (APC) tumor suppressor gene and activation of the KRAS oncogene are implicated in the pathogenesis of colorectal cancer. Mice harboring a germline Apc Min mutation or intestine-specific expression of the KRAS V 12gene have been developed. Both mouse strains develop spontaneous intestinal tumors, including adenoma and carcinoma, though at a different age. The zinc finger transcription factor Krüppel-like factor 5 (KLF5) has previously been shown to promote proliferation of intestinal epithelial cells and modulate intestinal tumorigenesis. Here we investigated the in vivo effect of Klf5 heterozygosity on the propensity of Apc Min /KRAS V 12double transgenic mice to develop intestinal tumors. Results At 12 weeks of age, Apc Min /KRAS V 12mice had three times as many intestinal tumors as Apc Min mice. This increase in tumor number was reduced by 92% in triple transgenic Apc Min /KRAS V 12/Klf5 +/- mice. The reduction in tumor number in Apc Min /KRAS V 12/Klf5 +/- mice was also statistically significant compared to Apc Min mice alone, with a 75% decrease. Compared with Apc Min /KRAS V 12, tumors from both Apc Min /KRAS V 12/Klf5 +/- and Apc Min mice were smaller. In addition, tumors from Apc Min mice were more distally distributed in the intestine as contrasted by the more proximal distribution in Apc Min /KRAS V 12and Apc Min /KRAS V 12/Klf5 +/- mice. Klf5 levels in the normal-appearing intestinal mucosa were higher in both Apc Min and Apc Min /KRAS V 12mice but were attenuated in Apc Min /KRAS V 12/Klf5 +/- mice. The levels of β-catenin, cyclin D1 and Ki-67 were also reduced in the normal-appearing intestinal mucosa of Apc Min /KRAS V 12/Klf5 +/- mice when compared to Apc Min /KRAS V 12mice. Levels of pMek and pErk1/2 were elevated in the normal-appearing mucosa of Apc Min /KRAS V 12mice and modestly reduced in ApcMin/KRAS V 12/Klf5 +/- mice. Tumor tissues displayed higher levels of both Klf5 and β-catenin, irrespective of the mouse genotype from which tumors were derived. Conclusions Results of the current study confirm the cumulative effect of Apc loss and oncogenic KRAS activation on intestinal tumorigenesis. The drastic reduction in tumor number and size due to Klf5 heterozygosity in Apc Min /KRAS V 12mice indicate a critical function of KLF5 in modulating intestinal tumor initiation and progression.