Peritonitis is the most frequent complication and a leading cause of discontinuation of peritoneal dialysis (PD). Intact epithelial lining, sufficient blood flow, and adequate immunologic responses are vital to eradicate infection. In long-term PD, various pathological changes such as denudation of peritoneal mesothelial cells, duplication of submesothelial and/or capillary basement membranes, submesothelial fibrin deposit, and peritoneal fibrosis have been reported. Causes of these changes of the peritoneum are multifactorial. Commonly used dialysis solutions that are acidic, hypertonic, containing high concentrations of glucose and lactate, contaminated by glucose and/or plastic degradation products are not biocompatible and may induce chronic immune reactions in the peritoneal cavity. Long-term exposure of the peritoneum to dialysis solutions, the peritoneal catheter, and recurrent episodes of peritonitis all contribute to peritoneal injury. In addition, long-term exposure of peritoneal cells such as macrophages, mesothelial cells, and fibroblasts to dialysis solutions may also alter the normal immunologic reactions against bacteria. Peritoneal concentrations of opsonins such as Ig, complement, and protease are approximately 1% of the serum levels and far below the level sufficient to eradicate bacteria due to continuous peritoneal lavage and dilution with dialysis solutions. Furthermore, glycation of IgG induces chronic activation of macrophages and decreases normal opsonic activities against bacteria. Fibrin deposits, collagen accumulation, and cellular desert of the peritoneum observed in long-term peritoneal dialysis patients may serve as a safe shelter for bacteria from contact with inflammatory cells and opsonin and delay eradication of bacteria. In conclusion, peritonitis is often more severe in patients on long-term PD. In this setting, peritonitis needs special attention to prevent life-threatening infection and further damage of the peritoneum.