Rare renal epithelial neoplasms have been recognized to have an angioleiomyoma or leiomyoma-like proliferation of stromal smooth muscle; however, the nature of these tumors and their relationships to other renal cell carcinomas are poorly understood. We analyzed 23 such tumors for their clinicopathological, immunohistochemical, and cytogenetic features using fluorescence in situ hybridization. Twelve showed a homogeneous combination of features and were reclassified as renal cell carcinoma with angioleiomyoma-like stroma. These were composed of neoplastic glandular structures lined by cells with mixed clear, pale, and eosinophilic cytoplasm forming occasional papillary tufts. The stroma resembled smooth muscle and often extended away from the epithelial component, entrapping perinephric fat or non-neoplastic renal elements. Immunohistochemistry showed the epithelium to have reactivity for: carbonic anhydrase IX, CD10, vimentin, cytokeratin 7, cytokeratin 34βE12, and PAX8 but not α-methylacyl-coA-racemase. The stroma labeled for smooth muscle (smooth muscle actin 3+, desmin 1+, caldesmon 3+) but not epithelial antigens. Neither component showed substantial reactivity for HMB45, melan-A, cathepsin K, or TFE3 protein. An interrupted, conspicuous layer of CD34-positive endothelial cells rimmed the epithelium, imparting a two-cell layer pattern resembling myoepithelial or basal cells. Chromosome 3p deletion and trisomy 7 and 17 were uniformly absent. Follow-up was available for three patients, none of whom experienced malignant behavior. Eleven tumors were excluded from this category and considered to be clear cell renal cell carcinoma with a reactive proliferation of smooth muscle (n=4) or tangential sectioning of the pseudocapsule (n=2), renal cell carcinoma unclassified (n=4), or clear cell papillary renal cell carcinoma (n=1). In summary, renal cell carcinoma with angioleiomyoma-like stroma is a distinct neoplasm with characteristic morphological, immunohistochemical, and molecular features, unrelated to clear cell renal cell carcinoma. The immunoprofile overlaps partly with that of clear cell papillary renal cell carcinoma, though morphology and reactivity for CD10 are points of contrast.