Introduction: Pleural effusion (PE) is common in clinical practice, with etiologies ranging from benign inflammatory conditions to metastatic malignancy. Cytology of pleural fluid is minimally invasive but may be limited by low cellularity and architectural loss. The cell block (CB) technique preserves tissue architecture and enables immunocytochemistry (ICC) and limited molecular assays, potentially improving diagnostic yield over conventional smear cytology (CSC). Materials and Methods: We conducted a prospective, hospital-based diagnostic accuracy study of consecutive adults with new or unexplained PE. Each sample underwent CSC and CB processing; CBs were subjected to ICC as indicated. Final etiologic diagnosis was based on clinicoradiologic correlation and/or histology. Primary outcomes were diagnostic yield and accuracy of CB vs CSC; secondary outcomes included incremental yield of ICC, sample adequacy, complications, and concordance with pleural biopsy/clinical gold standard. Results: Among 220 patients (mean age 58.6±13.1 years; 54.5% male), 138 (62.7%) had malignant pleural effusion (MPE). Diagnostic yield: CSC 56.5%, CB 68.1%, CB+CSC 75.9% (p<0.001 vs CSC). In MPE, sensitivity was 71.7% (CB) vs 62.3% (CSC), with similar specificity (both ≥97%). ICC increased malignant detection by an absolute 7.2% and enabled site-of-origin assignment in 64.7% of previously “positive NOS” cases. Concordance with pleural biopsy/definitive diagnosis was 89.4% (CB) vs 82.4% (CSC). Inadequacy was lower with CB (6.4% vs 12.7%). No CB-related adverse events occurred. Conclusion: The cell block technique significantly improves overall diagnostic performance for pleural effusions, particularly for malignancy, and adds clinically meaningful information via ICC. Routine integration of CB alongside CSC is recommended.