Cytology allows the diagnosis of malignant mesothelioma (MM) from effusions with high specificity but low sensitivity. Conversely, elevated levels of hyaluronic acid (HA) in effusions are sensitive indicators of MM, although specificity is insufficient. We studied whether the cytological diagnosis of MM could be improved by HA analysis. HA was analysed in patients with histologically confirmed MM (n=162), adenocarcinoma or other malignant tumours (n=100) and in 90 patients with benign pleural diseases. In 77 out of 162 effusions, all, and in 33 some, cytological criteria of MM were satisfied. The cut-off value of HA showing maximum diagnostic reliability (86%) regarding MM was 30 mg/l (sensitivity 87%, specificity 86%). A HA value of 100 mg/l yielded 39 and 98%, respectively. Seventy three out of 77 patients with cytological findings indicative of MM showed HA levels greater than 30 mg/l as well as 27 of 33 patients with suspicious lesions. These 100 patients were correctly recognised as having MM. The addition of HA analysis to cytology, requiring all or some criteria of MM as positive, increased sensitivity for MM from 48 to 71-91%, whereas specificity only slightly decreased to 94-96%. We conclude that the combined cytological and HA analysis of pleural effusions had the potential to improve the diagnosis of MM.