Background: Primary mediastinal rhabdomyosarcoma (RMS) unassociated with germ cells, teratomatous or malignant epithelial components are extremely rare, tend to have large size, important local invasion at diagnosis, with aggressive behavior and poorer prognosis. Case Report: We present an extremely rare case of primary mediastinal RMS with malignant pleural effusion in a fourteen year old female patient with emphasis on cytological examination of the pleural fluid, diagnostic difficulties and differential diagnosis. Cellular smears showed numerous discretely scattered reactive mesothelial cells admixed with numerous neutrophils and lymphocytes. In addition there was a distinct second population of neoplastic cells essentially singly scattered and occasional dyshesive clusters seen initimately mingled with reactive mesothelial and inflammatory cells. Conclusion: This case elucidates the potential pitfall in identifying the single scattered neoplastic cells from initimate admixture with reactive mesothelial cells and highlights the importance of careful cytomorphologic evaluation with adjunct immunocytochemistry for myogenin to accurately diagnose metastatic RMS in effusion specimens.