Mutations of the Kristen ras (K-ras) gene have been implicated in the pathogenesis of human lung cancer, especially adenocarcinoma, and have been proposed to be a prognostic factor. The K-ras mutation in codon 12 is detectable even in cell-free fluids by using the enriched polymerase chain reaction (PCR) technique. On the other hand, based on experimental results, the rho A mutation in codon 14 is also proposed to be oncogenic as observed in the K-ras mutation. Malignant pleural effusion is a common complication of lung cancer. We studied the point mutation of K-ras codon 12 and rho A codon 14 using enriched PCR in specimens of pleural effusion. Forty patients with pleural effusion were enrolled in this study. The causes of pleural effusion were non-small cell lung cancer (18 cases), small cell lung cancer (6 cases), malignant mesothelioma (2 cases), metastatic lung tumor (5 cases), thymoma (1 case), malignant lymphoma (1 case), and pleuritis tuberculosa (7 cases). The K-ras mutation was detected in 4 of 14 cases with adenocarcinoma, 1 of 3 cases with squamous cell carcinoma, 1 of 1 case with large cell carcinoma, and 1 of 5 cases with metastatic lung tumor, respectively. The rho A mutation was not detected in any pleural effusion examined in this study. Our study demonstrates the usefullness of pleural effusion as a clinical specimen for a search of point mutation of oncogenes. The K-ras codon 12 mutation is readily detected in pleural effusion, and the demonstration of this mutation has potentially important implications for the diagnosis of malignant pleural effusion.