Critical factors responsible for the recurrence of keratocystic odontogenic tumor (KCOT) were examined. Methods: The clinicopathological features were retrospectively studied in 74 patients with 75 sporadic KCOTs. From the 75 KCOTs, 23 were examined for the expression of Sonic Hedgehog (SHH), Patched and Smoothened (SMO) by immunohistochemistry. Results: Recurrence in multilocular lesions was more frequent than in unilocular lesions. Nine (64%) of 14 multilocular lesions recurred, in contrast to 2 (7%) of 27 unilocular lesions (p = 0.0350). The average length of recurrent lesions (62.8 ± 6.5 mm) was larger than that of nonrecurrent lesions (43.0 ± 4.0 mm; p = 0.0363). The immunoreactivity of proliferation-related SMO in KCOTs with recurrence was higher than that of those without recurrence (p = 0.0475), whereas the expressions of a ligand, SHH, and an inhibitory receptor, Patched, were not associated with KCOT recurrence. The expressions of SHH and SMO showed inverse correlation in whole KCOT (p = 0.0318). Conclusion: These findings suggest that recurrence of KCOT is associated with multilocular large lesions and high SMO expression.