The cytologic diagnosis of malignancy is frequently straightforward. For difficult cases, multiple immunostains and immunostain panels have been investigated without consensus. beta-human chorionic gonadotropin (hCG) has been reportedly expressed in malignancies, but not in normal tissue. HCG also has been reported as a specific marker of metastases in serous fluids when detected with laboratory assays. We investigated the clinical utility of hCG in this cytologic setting. A total of 97 cases of benign and malignant effusions were studied. Each case was immunostained with monoclonal hCG using the avidin-biotin technique and diaminobenzidine as a chromogen. Additionally, a mucicarmine stain was performed on most cases. Cases were evaluated for hCG expression and mucin in a blinded fashion. After the cases were reviewed, the diagnoses were unblinded and staining patterns were evaluated. Of the 47 benign cases studied, 23 (49%) exhibited immunoreactivity to hCG in at least 5% of mesothelial cells present. In contrast, 28 of 44 (64%) adenocarcionomas exhibited a similar degree of immunostaining. In all, 21 (48%) of the adenocarcinomas were also positive for mucin; five of these mucin-positive cases were negative for hCG. The combination of mucin and hCG detected 33 of 44 (75%) adenocarcinomas. We conclude that hCG lacks the specificity for malignant cells to be of clinical use in effusion cytology.