Soft-tissue lesions pose an intimidating challenge to diagnostic interpretation by fine-needle aspiration cytology. to better characterize such aspirates, we investigated a subgroup of lesions which yielded a large amount of chondromyxoid and myxoid stroma (CMS). Thirty-three cases (22 malignant lesions, 11 benign lesions) in which CMS was a prominent feature of the smears were studied. the most common malignant neoplasms were extraskeletal chondrosarcoma (6 cases), myxoid liposarcoma (6), and malignant fibrous histiocytoma (5). the benign entities consisted of ganglion cyst (4), myxoma (3), and neurofibroma (2). of the aspirates from 22 malignant neoplasms, 15 (68%) contained opaque stroma, and in 18 (81%) the stroma was distributed as discrete clumps or fragments; all extraskeletal chondrosarcomas and chordomas contained these features. Additionally, in five of six chondrosarcomas the matrix exhibited cells within lacunae. Except for a tracheal chondroma which extended into the adjacent soft tissue, no benign aspirates had all three of these cytologic features. Twenty-three aspirates (70%) were moderately or highly cellular; all but two of these were malignant. Moderate to marked nuclear atypia occurred in 13/22 (59%) malignant and 1/11 (9.0%) benign aspirates. With a few exceptions, aspiration smears of benign lesions with abundant CMS were characterized by low cellularity, semitransparent amorphous stroma, and lack of nuclear irregularity. Recognition of variations in the character of the background material in addition to traditional cytologic criteria can aid in the diagnosis of benign and malignant chondromyxoid and myxoid aspirates of soft tissue. © 1995 Wiley- Liss, Inc.