We examined the expression pattern of cyclooxygenase-2 (COX-2) and c-kit in uterine smooth muscle neoplasms and tried to determine the role of these markers in differential diagnosis. Archival tissue from 64 patients with uterine smooth muscle neoplasms (20 leiomyomas (LMs), 22 atypical leiomyomas (ALMs), and 22 leiomyosarcomas (LMSs)) was immunostained with antibodies against estrogen (ER) and progesterone receptors (PR), COX-2 and c-kit. 7 of 20 LM cases and 5 of 22 ALM cases were immunopositive for COX-2, whereas none of the LMS cases stained immunopositive (p <= 0.05). 4 of 20 LM cases and 5 of 22 ALM cases were immunopositive for c-kit, whereas 15 of 22 LMS cases showed c-kit immunopositivity (p <= 0.05). In conclusion, very few LMs and ALMs show COX-2 immunopositivity. LMSs usually do not express COX-2. COX-2 expression in smooth muscle tumors is not a prominent feature. Therefore, COX-2 inhibitors may not be useful in LMS therapy. C-kit was significantly expressed in uterine LMSs.