Osteosarcomatous differentiation in phyllodes tumors is uncommon. The clinicopathologic features of 22 such cases in our files were retrospectively reviewed to evaluate the prognostic significance of this rare neoplasm. All patients were women between 40 and 83 years of age (mean, 60 years). Most (73%) presented with a palpable mass. None had prior irradiation to the breast or chest region. Patients were treated with excisional biopsy (N = 4), partial mastectomy (N = 1), or mastectomy (N = 17). All axillary nodes, dissected in 11 patients, were free of tumor. Two patients had extramammary spread at diagnosis. The neoplasms measured 1.9-15 cm (mean, 6.4 cm); 54% were grossly circumscribed or multilobulated. The osteosarcomatous component was classified as fibroblastic (N = 11), osteoclastic (N = 6), or osteoblastic (N = 5) and occupied a variable percentage of the phyllodes' stroma ranging from -25% to essentially 100% of the neoplasm. Of 21 patients with available follow-up, 11 (52%) were alive at a median follow-up of 44 months. Nine patients (43%) developed locally recurrent (N = 1) or metastatic (N = 8) disease. Metastases were clinically apparent within 1 year of diagnosis in all eight patients; seven died within 12 months of detection of initial metastasis. By univariate analysis, gross tumor size and osteosarcoma subtype significantly correlated with prognosis. In a multivariate analysis, neither of these factors were independent prognosticators. Phyllodes tumors with an osteosarcomatous component are potentially aggressive neoplasms, particularly when large (>5 cm) or associated with an osteoclastic or osteoblastic osteosarcoma. Complete excision without axillary dissection is advised.