Although the fusion proteins EWS-ETS are uniquely associated with Ewing's sarcoma and have been shown to have transformational properties, they are not the only determinants of oncogenesis. Therefore, before molecular-based therapy can be initiated, a better understanding of the molecular network specific to Ewing's sarcoma is mandatory. Specimens from 31 patients with Ewing's sarcoma were analyzed immunohistochemically. We found that human telomerase reverse transcriptase was expressed highly (78%) in Ewing's sarcoma. The mean followup was 7 years (range, 1-21 years), and human telomerase reverse transcriptase expression was correlated with outcome. Because we did not find an association between expression pattern and survival, human telomerase reverse transcriptase may not serve as a tumor marker in Ewing's sarcoma. However, the human telomerase reverse transcriptase promoter is shown to be activated by the fusion proteins. Therefore, transcriptional regulation via EWS-ETS may account for the high human telomerase reverse transcriptase expression in Ewing's sarcoma.