Background: In vitro studies have shown that pH and glucose degradation products (GDPs) in the dialysate are determinant factors for the biocompatibility of peritoneal dialysis (PD) treatment. The present study was thus designed to evaluate whether a newly developed PD solution, which features neutral pH levels and a low GDP concentration, influences tissue damage of the peritoneal membrane in an in vivo setting, and which factor is more critical to the histological changes. Methods: Rats were injected 3 times per day during 1 or 4 weeks with 10 ml of various PD fluids (group G, acidic pH, high GDPs; group S, neutral pH, low GDPs; or group A, acidic pH, low GDPs). When the experimental period was over, the mesothelial cell monolayers of the animals were taken and studied with population analysis, and peritoneal membranes were obtained from the abdominal wall for immunohistochemical examination with proliferating cell nuclear antigen (PCNA) and for measurement of thickness of the peritoneal specimens. Results: The density of the mesothelial cell monolayer and the number of fibroblast-like cells in group S were significantly less than in group G at 1 and 4 weeks’ injection. PCNA-positive nuclei in group S were significantly less than in group G for only the 1-week injection set (group G, 2.03 ± 0.95; group S, 0.85 ± 1.18 nuclei/1 × 104 µm2). At 4 weeks, the peritoneal thickness of group S (6.32 ± 0.53 µm) was significantly less than that of group G (7.94 ± 0.77 µm), There was no significant difference between groups S and A throughout the whole study period except for the result of the number of fibroblast-like cells. Conclusion: These results indicate that a PD solution with a neutral pH and low GDPs proved more biocompatible with the peritoneal membrane than a solution with an acidic pH and high GDPs. Furthermore, the level of the GDPs has more impact on tissue damage of the peritoneal membrane than the pH in the short term.