Background: Growth factors including EGF have emerged as potential therapeutic options for patients with surgical short gut syndrome. The potential augmentation of the adaptive response by EGF makes it an appealing therapy to promote intestinal autonomy. Crypt epithelium responds to small bowel (SB) resection with increased proliferation and fissioning. EGF augments the intestinal epithelial cell (IEC) responses to intestinal resection although its role in regulating β-catenin is unclear. To examine the potential that EGF-induced PI3K mediates the epithelial response to β-catenin activation in ICR, we utilized an inducible genetic model of intestinal epithelial specific deletion of Class IA PI3K p85α AhCre/pi3kr1 ). Our laboratory demonstrated cross-talk between PI3K and the Wnt/β-catenin signaling pathways in inflammatory bowel disease tissue. Previous data from Clevers and colleagues showed that the proliferative responses originate in intestinal stem cells (ISC) and are dependent on Wnt/β-catenin signaling. Here we test the notion that EGF stimulates IEC via β-catenin activation after ICR through PI3K pathway. Design/Methods: C57BL/6 wild type (WT) mice and AhCre/pi3kr1 animals underwent sham surgery, ICR, or no surgery. All animals were given 50 ug/kg/day of rEGF in osmotic pumps immediately after the surgery. Five days later, SB morphometrics, immunohistochemistry (IHC) for BrdU incorporation (2hr), phospho(p) AKT(Thr308), and pBcatenin(ser552) and western blots of purified IEC proteins including cleaved caspase-3 and nuclear total β-catenin were performed. Results: Compared to EGF-treated sham, EGF-treated ICR mice have increased crypt length (63.3 ± 7 vs 118.3 ±2 8.9 μm, p< 0.05), BrdU incorporation, pAKT(Thr308), pβ-catenin(ser552) by IHC, and nuclear total β-catenin (WB). Data on AhCre/pi3kr1 ICR mice revealed reduced crypt length (118.3±28.9 vs. 67.1 ± 15.5 μm, p< 0.05 ), incorporation of pBcatenin(ser552) (1.43 ± 0.58 vs. 0.85 ± 0.19 counts/crypt, p< 0.05), and a 90% reduction of nuclear total β-catenin by WB. Interestingly, BrdU incorporation in AhCre/pi3kr1 ICR mice was similar to EGF-treated ICR alone, whereas cleaved caspase-3 (WB) doubled, suggesting enhanced apoptosis attenuated the observed induction of IEC proliferation. Conclusions: These data indicate that the epithelial response to ICR in EGF-treated mice enhanced crypt length and IEC proliferation along with PI3K and β-catenin signaling. Furthermore, data indicate that PI3K enhanced IEC crypt lengths, β-catenin activation, and cell survival. Thus, we propose that enhanced IEC PI3K signaling in short bowel patients may facilitate the recovery of absorptive surface through epithelial restitution.