Introduction: The usefulness of sericin as pleurodesis agent has previously been described. Present study aims to compare sericin pleurodesis regarding success, effectiveness, tolerability, and side-effects. Methods: Adult, 12-week-old Wistar-albino rats (n = 60), divided to five groups as sericin, talcum-powder, doxycycline, silver-nitrate and control. Agents were administrated through left thoracotomy, rats sacrificed twelve-days after. Results: Highest ratio of collagen fibers was observed in sericin group, and the intensity was higher than talcum-powder group (p < 0.05). Compared to silver nitrate, sericin group displayed better mesothelial reaction, and multi-layer mesothelium was also better (p < 0.05). Foreign body reaction and emphysema were less frequent in sericin group (p < 0.05). The presence of biological tissue in parenchyma was less prominent in sericin group (p < 0.05). Foreign body reaction on thoracic wall was less common in sericin group (p < 0.05). Presence of biological tissue glue in thoracic wall was less prominent in sericin group (p < 0.05). Glomerular degeneration was lower in sericin group compared to the silver nitrate group (p < 0.05), and tubular degeneration was less common in sericin group than talcum group (p < 0.05). Pericarditis was less common in sericin group compared to the other groups (p < 0.05). Conclusion: As an intrinsic, natural glue protein, sericin protects the lung parenchyma and tissues, and its glue-like characteristics enable pleurodesis. The success of sericin in pleurodesis was demonstrated in the present study based on investigations of the pleurae. Being cost-effective and better tolerated agent associated with a low potential of side effects, sericin is more effective, less expensive and provides more lung parenchyma protection.