Cell cycle regulatory protein expression by immunohistochemical assay may have diagnostic utility in the distinction of uterine leiomyosarcoma from leiomyoma variants. p16, p21, p27, and p53 protein expression was evaluated by immunohistochemistry on 44 atypical leiomyomas (mean follow-up, 50.8 mo), 16 leiomyosarcomas (mean follow-up, 29.7 mo), and 8 cellular leiomyomas (mean follow-up, 22.6 mo). Nuclear staining was semiquantitatively scored on 1 representative section per case as negative (0%), focal (>0% to 33%), patchy (>33% to 66%), or diffuse (>66%). In addition, staining intensity was noted as weak, moderate, or strong. Proliferative index was gauged by Ki-67 and PHH3 immunohistochemical staining. One of 35 atypical leiomyoma patients with follow-up data developed an extrauterine recurrence 25.7 months after hysterectomy, whereas a second had intrauterine recurrence 24.9 months after myomectomy. Seven of 8 patients with leiomyosarcoma with follow-up had recurrence within the follow-up period, whereas there were no recurrences in patients with cellular leiomyoma. The Ki-67 proliferation index ranged from 0% to 25% in atypical leiomyoma (mean, 2%) and 6% to 50% in leiomyosarcoma (mean, 25%) with 0% to 10% in cellular leiomyoma (mean, 3%), whereas the PHH3 proliferation index ranged from 0% to 3% in atypical leiomyoma (mean, <1%) and 0% to 10% in leiomyosarcoma (mean, 2%) with 0% to 2% in cellular leiomyoma (mean, <1%). The atypical leiomyoma with extrauterine recurrence was diffusely positive for p21, but showed only weak focal (<33%) staining for all other cell cycle markers. Uterine atypical leiomyomas, cellular leiomyomas, and leiomyosarcomas demonstrate a heterogenous pattern of cell cycle regulatory protein expression. Caution should be exercised in distinguishing leiomyosarcoma from atypical leiomyoma variants on the basis of cell cycle protein expression alone. In our study, cell cycle markers were not useful for predicting recurrence in atypical leiomyoma.