Goblet cells are important in the maintenance of the epithelial cell population in the airway, defense against injury and storage and release of mucins, which can protect the surface epithelial layer. In our rat tracheal model of acute rejection, there is injury and loss of respiratory epithelium in allografts. This loss of epithelium is associated with obliteration of the airway lumen. In small bowel allografts, studies have shown that the loss of goblet cells is an important histologic feature of rejection. The aims of this study were: (i) to examine for the first time the close time-course of goblet cell proliferation in acute rejection; and (ii) to compare the isograft vs. allograft morphometric changes associated with epithelial damage. Methods: Heterotopically transplanted rat tracheas (n = 45) were harvested at days 3, 5, 7, 10 and 12. Hematoxylin & eosin (H&E), Alcian blue and PAS staining was completed. Computerized image analysis was used to assess epithelial coverage. The mean number of PAS-positive goblet cells counted at 40×/field was determined, and 10 fields were counted per tracheal section. Results: There was a significant decrease in the number of goblet cells in the allografts between days 5 and 12 (p < 0.006). In the isografts, there was a gradual increase from day 3 to 10 (p < 0.05), then a sharp fall from day 10 to 12 (p < 0.03). In isografts from day 7 to 10, the goblet cell number increased, while the percentage respiratory epithelium remained the same. The percentage respiratory epithelial coverage and the number of goblet cells showed a direct correlation in the allografts (r2 = 0.57). Conclusions: Our study shows, for the first time, that goblet cell proliferation occurs in the epithelial repair phase in isografts, whereas in allografts the goblet cells are lost and do not recover.