Most patients with malignant mesothelioma (MM) present with an effusion, but distinguishing malignant from reactive mesothelial cells by conventional cytology may be difficult. We investigated the possibility of identifying clonal cytogenetic aberrations in pleural or peritoneal fluid from 10 patients with a clinical suspicion of MM. Direct metaphase harvests and short-term cultures were performed on fresh fluid. Clonal cytogenetic aberrations indicative of malignancy, with findings previously reported in association with mesothelioma, were found in all patients; these included del(1p), del(3p) and del(22q). Cytologic examination of the effusions showed malignant cells consistent with MM in 5 patients and atypical mesothelial cells suggestive of MM in 4. In one case the cytology of several samples of pleural fluid was within normal limits. Subsequent histology confirmed the diagnosis of MM in 9 of the 10 patients; medical complications precluded tissue biopsy in the 10th. We conclude that the cytogenetic analysis of effusions may be a useful and reliable adjunct to cytology in the diagnosis of MM.