We initiated a phase II study with combination chemotherapy consisting of cisplatin, etoposide and bleomycin in a subset of patients with carcinomas of unknown primary site characterized by the presence of at least one of the following criteria: 1) age below 50 years; 2) clinical evidence of rapid tumour growth; 3) tumour located predominantly in a midline distribution; 4) good response to previous administered radiotherapy. In 34 evaluable patients an objective response rate of 53% (95% confidence limits 35%-70%) was achieved. For patients with poorly differentiated adenocarcinomas the response rate was 35%, and, in most instances, of short duration. A response rate of 79% including complete responses and long-term survivals was achieved in patients with undifferentiated carcinomas. This difference in response rate was statistically significant (p = 0.02). No supplementary prognostic factors predicting response to chemotherapy could be identified. One patient with an initial diagnosis of undifferentiated carcinoma proved to have a malignant lymphoma after additional immunohistochemical investigation. Until a better characterization of this syndrome is possible patients with undifferentiated carcinomas of unknown primary site should be challenged with cisplatin-based chemotherapy.