Background: The diagnosis of atypical cases in the effusion cytology sample often poses a challenge to the cytologists. Aims and Objectives: We evaluated the diagnostic role of MOC31 in the metastatic adenocarcinoma in effusion fluid. Materials and Methods: The cytological examination and MOC31 immunostaining in the cell block sections were carried out in 64 cases of serous effusion. A total of 23 cases showed atypical cytology, out of which suspicious for malignancy (SFM) and atypia of undetermined significance (AUS) were 19 and 4 cases, respectively. In these cases, we also performed calretinin immunostaining. The cytological features, results of MOC31 immunostaining, and follow-up data were correlated to find out the sensitivity and specificity of MOC31 immunostaining in the diagnosis of metastatic adenocarcinoma. Result: The sensitivity and specificity of MOC31 were 100%. MOC31 detected all the cases of metastatic adenocarcinoma. MOC31 showed strong positivity in 19 cases of SFM. All these cases had a malignant outcome in histopathology or follow-up data. In AUS cases, MOC31 immunostaining was negative with a benign outcome. In all the atypical but malignant cases calretinin stain showed diffuse cytoplasmic and nuclear positivity. In contrast, MOC31 showed strong membranous positivity and occasionally cytoplasmic positivity. Conclusion: MOC31 is an excellent marker of metastatic adenocarcinoma in the serous effusion. The membranous positivity of MOC31 and negative calretinin immunostaining are helpful in atypical cytological cases to avoid the diagnostic dilemma. The MOC31 positivity is significantly useful in discrete atypical cells which are more challenging to recognize.