Clear cell sarcomas and metastatic soft tissue melanomas. A flow cytometric comparison and prognostic implications. Eleven soft tissue clear cell sarcomas (CCS) were examined flow cytometrically for their DNA content with a correlation of the DNA with the patients' survival. Diploidy was expressed in six sarcomas and it conferred a longer survival (mean, 68.6 months) than aneuploid sarcomas (mean, 8.2 months). For comparison, 13 metastases to soft tissues from cutaneous melanomas were assessed by flow cytometric study. The aneuploid neoplasms of both entities were categorized into low and high degree based on extent of the DNA index (DI). Low degree was defined by a DI of less than or equal to 1.5 and high degree by a DI of greater than 1.5. Significant differences in DNA content between CCS and metastatic melanomas were observed. Melanomas were preponderantly aneuploid (11/13) of high degree (mean DI, 1.7) whereas CCS manifested more diploidy (six of 11) and their aneuploidy was of a low degree (mean DI, 1.2; P = 0.001). Clear cell sarcomas and melanomas were also examined for their immunoreactivity to S-100 protein and HMB-45 antigen. All CCS reacted with S-100 protein and HMB-45. In CCS the reactions were diffuse for both in six tumors, diffuse with HMB-45 and moderate to S-100 protein in three tumors and diffuse with S-100 and moderate with HMB-45 in two tumors. All melanomas reacted diffusely to S-100 protein except for one heavily pigmented tumor which reacted only focally. The reaction to HMB-45 was diffuse in nine and focal in three melanomas. These data suggest that measurements of DNA content in CCS may be valuable in predicting clinical outcome and that there are quantitative differences in DNA content between CCS and metastatic melanoma in soft tissues. 