Several human lung tumor cell lines derived from large cell, squamous cell, and small cell carcinomas, as well as from mesotheliomas of the lung have been investigated for their gene expression and secretion of urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitors 1 and 2. All bronchogenic non-small cell carcinoma-derived cell lines studied could produce either plasminogen activators, their inhibitors, or both components, whereas in small cell lung carcinoma cell lines and cell lines derived from mesothelioma of the lung, no substantial amounts of any of these substances were synthesized. In detail, a large cell carcinoma-derived cell line, LCLC 97TM1, constitutively secreted large amounts of plasminogen activator. Northern blot analysis revealed RNA specific for u-PA and t-PA. Another large cell carcinoma-derived cell line, LCLC 103H, secreted smaller amounts of plasminogen activator and, additionally, plasminogen activator inhibitor. Specific mRNAs for u-PA and plasminogen activator inhibitors 1 and 2 were found in this cell line. In contrast, squamous cell carcinoma-derived cell lines secreted plasminogen activator only after treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate; enhanced levels of u-PA, t-PA, and plasminogen activator inhibitor 1 mRNAs could then be demonstrated. The different expression of the plasminogen activator enzyme system distinguishes cell lines derived of non-small cell lung carcinoma from those of small cell lung carcinoma and may also reflect significant differences in the biological behavior of these tumor types.