Aggressive angiomyxoma is a rare mesenchymal neoplasm, which almost always occurs in the vulvovaginal region and which exhibits a marked tendency for local recurrence after excision. A wide range of other mesenchymal lesions occur in this region, which potentially mimic aggressive angiomyxoma to a variable extent. Because rearrangement of the HMGA2 gene has been shown in a significant percentage of aggressive angiomyxomas, we examined the expression of HMGA2 protein in this neoplasm and in a large number of other mesenchymal lesions occurring at this site, including many which were referred with a possible diagnosis of aggressive angiomyxoma. There was positive staining of tumor cell nuclei, mostly with a diffuse distribution, in all but 2 aggressive angiomyxomas (n=12). Blood vessel endothelial cells within the neoplasms, entrapped tissues, and surrounding normal tissues were negative. Ten of 23 leiomyomas were positive, as were occasional other neoplasms. Based on our study, we conclude that HMGA2 is positive in most aggressive angiomyxomas and is useful in diagnosis as most mesenchymal lesions which closely mimic this are negative. However, caution should be exercised as some other vulvovaginal mesenchymal lesions, especially, but not exclusively leiomyomas can be HMGA2-positive. As well as being of value in primary diagnosis, HMGA2 is useful in evaluating margins and in reexcision specimens of aggressive angiomyxoma in identifying foci of residual or recurrent tumor.