Background: The aim of present study is to compare the effectiveness, side-effect potential of different doses of sericin pleurodesis. Methods: Adult, male, 12-week-old, Wistar-albino rats (n = 52), were randomly-divided into four-groups, referred to A, B, C and D. Sericin was administrated at different doses through left thoracotomy, with 15 mg sericin to Group-A, 30 mg to Group-B and 45 mg to Group-C. Group-D was assigned as control group. The rats were sacrificed 12 days later. Left-hemithorax, heart, liver and kidney were examined pathologically. Results: No foreign body reaction in the parenchyma was observed in any of the rats, while emphysema was least common in Group-B (P <.05). Multi-layer mesothelium of both pleura was most common in Group-B, while fibrosis and fibrin organization within the visceral-pleura was more successful in all of sericin treated groups than in control group (P <.05), with neither Group-A, Group-B nor Group-C being superior to each other. In the examination of collagen fibers using Masson's trichrome, “dense collagen fibers” were found in all three sericin treated groups, and differences between Groups-A, -B, -C and the control group were significant (P <.05). The probability of observing pyknotic nucleus and balloon degeneration in liver increased with increasing sericin doses (P <.05). Glomerular degeneration in kidney and the findings of pericarditis were most common in Group-C (P <.05). Conclusion: The target should be to maximize efficacy while minimizing the likelihood of side-effects. The intrapleural administration of sericin 30 mg performs better due to multi-layer mesothelial reaction being higher and emphysema being lower in Group-B, to the fewer side-effects affecting the kidney and heart, and liver toxicity not being higher.