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The aim of this study was to investigate whether decompression treatment induces changes in the histology or biologic behavior of keratocystic odontogenic tumor (KCOT).Seventeen patients with KCOT underwent decompression treatment with or without enucleation. Histologic evaluation and immunohistochemical expression of p53, Ki-67, and Bcl-2 were analyzed by using conventional microscopy.KCOT showed significantly increased fibrosis (P = .01) and a subjective reduction in mitotic activity (P = .03) after decompression. There were no statistically significant changes in the expression of proliferation markers. An increase in daughter-cysts or epithelial rests was seen after decompression (P = .04). Recurrence was noted in four of 16 cases, and expression of p53 was strongly correlated with prolonged duration of treatment (P = .01) and intense inflammatory changes (P = .02).Structural changes in the KCOT epithelium or capsule following decompression facilitate surgical removal of the tumor. There was no statistical evidence that decompression influences expression of proliferation markers in the lining, indicating that the potential for recurrence may not be restricted to the cellular level. The statistically significant increase of p53 expression with increased duration of treatment and increase of inflammation may also indicate the possibility of higher rates of recurrence with prolonged treatment and significant inflammatory changes.