Following massive small bowel resection (SBR) in mice there are sustained increases in crypt depth and villus height, resulting in enhanced mucosal surface area. The early mechanisms responsible for resetting and sustaining this increase are presently not understood. We hypothesized that expansion of secretory lineages is an early and sustained component of the adaptive response. This was assessed in the ileum by quantitative morphometry at 12 h, 36 h, 7 d and 28 d and by quantitative RT-PCR of marker mRNA's for proliferation and differentiated goblet, Paneth cell and enterocyte genes at 12 h following 50% SBR or sham-operation. As predicted, SBR elicited increases of both crypt and villus epithelial cells which were sustained though the 28 d of the experiment. Significant increases in the overall number and percentage of both Paneth and goblet cells within intestinal epithelium occurred by 12 h and were sustained up to 28 d following SBR. The increases of goblet cells following SBR were initially observed within villi at 12 h, with marked increases occurring in crypts at 36 h and 7 d. Consistent with this finding, qRT-PCR demonstrated significant increases in the expression of mRNAs associated with proliferation (c-myc) and differentiated goblet cells (Tff3, Muc2) and Paneth cells (lysozyme), whereas mRNA associated with differentiated enterocytes (sucrase-isomaltase) remained unchanged . From these data we speculate that early expansion of intestinal secretory lineages within the epithelium of the ileum occur following SBR, possibly serving to amplify the signal responsible for initiating and sustaining intestinal adaptation.