Objective: The aim of our study was to identify the diagnostic value of insulin-like growth factor-II mRNA-binding protein 3 (IMP3) in distinguishing metastatic adenocarcinoma cells (MAC) from reactive mesothelial cells (RMC) in effusions. We also investigated the role of IMP3 as a prognostic indicator for patients with malignant effusion. Study Design: A total of 156 cell block specimens, including 116 malignant effusions with MAC and 40 benign effusions with RMC, were subjected to immunocytochemical staining for IMP3. Results: Immunocytochemical studies showed positive staining for IMP3 in 91 of 116 (78.4%) cases of MAC and in 3 of 40 (7.5%) cases of RMC. With regard to distinguishing MAC from RMC, the IMP3 reactivity was found to be 78.4% sensitive and 92.5% specific with a positive predictive value of 96.8% and a negative predictive value of 59.7%. Diffuse IMP3 expression (>25%) in MAC from patients with gastric adenocarcinoma was associated with shorter survival (p = 0.001). Conclusion: Our data suggest that IMP3 is a helpful marker for differentiating MAC from RMC, and that diffuse IMP3 expression is a poor prognostic indicator in patients with gastric adenocarcinoma and malignant effusion.