Many characteristics of epithelial cells are moderated through interactions with adjacent stromal components. In tumor cells, abnormal interactions between cells and stroma can be important determinants of malignant progression, including invasion and metastasis. Evidence has accumulated for the importance of the interaction between the stromal component hyaluronic acid (HA) and its major cell surface receptor, CD44S, in invasion and metastasis. Because malignant mesotheliomas are characterized by the accumulation of abundant HA, we chose to evaluate this group of tumors for the presence of stromal HA, cellular HA, and CD44S, the CD44 molecule that is principal receptor for HA. For comparison, we also analyzed a group of lung adenocarcinomas and several reactive mesothelial hyperplasias, two entities that are often included in the differential diagnosis of malignant mesothelioma. In 10 of 12 (83%) reactive mesothelial hyperplasias, 14 of 22 (63%) mesotheliomas, and 9 of 26 (34%) adenocarcinomas, membrane immunoreactivity with CD44S could be demonstrated, a difference that was statistically significant between adenocarcinomas and reactive mesothelial hyperplasias (p = 0.0128) and approached significance between adenocarcinomas and mesotheliomas (p = 0.0810). Adenocarcinomas, when positive, were more likely to show more focal staining compared with the more common diffuse staining in mesotheliomas. Although a high percentage of samples from all three groups showed stromal HA, cellular HA was much more common in mesothelioma cells (20 of 22; 91%) than in either adenocarcinomas (4 of 26; 15%, p < 0.0001) or mesothelial hyperplasias (2 of 12; 17%, p = 0.0001). Comparison of HA staining with standard immunohistochemical markers is needed to demonstrate the diagnostic utility of this stain.