Benign metastasizing leiomyomas are rare tumors, which are typically found in the lungs and, thus, might be confused with leiomyosarcomas. Further, it is not clear whether the term "benign metastasizing leiomyoma" is a misnomer and whether these lesions actually represent low-grade malignant tumors that have a low proliferation index. Micro-RNAs (miRNAs) are small noncoding RNAs, which repress translation. The altered expression of miRNAs has been strongly correlated with the malignant phenotype. In this study, the histologic features, Ki67 index, p53, bcl-2, and miRNA expression were studied in 15 leiomyosarcomas (11 primary lesions and 4 metastases), 8 leiomyomas, and 10 cases of benign metastasizing leiomyoma (9 pulmonary lesions and 1 primary uterine lesion). As expected, the Ki67 index for the benign metastasizing leiomyomas was equivalent to that for the leiomyomas and statistically less than that for the leiomyosarcomas. The mean index was 2.3% (range: 0.9% to 8.8%) for the leiomyomas and 3.4% (range: 0.7% to 8.1%) for the benign metastasizing leiomyomas compared with 28.6% (range: 14.4% to 62.0%) for the leiomyosarcomas (P<0.025). The miRNA, miR-221, which has been associated with a variety of cancers, was detected by in situ hybridization in 13/15 leiomyosarcomas, 0/8 leiomyomas, and 0/10 benign metastasizing leiomyomas. In conclusion, benign metastasizing leiomyomas are indeed most likely benign lesions, and up-regulation of miR-221 expression is an accurate way to differentiate leiomyosarcoma from benign metastasizing leiomyoma.