Exposure to non-physiological solutions during peritoneal dialysis (PD) produces structural alterations to the peritoneal membrane and ultrafiltration dysfunction. The high concentration of glucose and glucose degradation products in standard PD fluids induce a local diabetic environment, which leads to the formation of advanced glycation end products (AGEs) that have an important role in peritoneal membrane deterioration. Peroxisome proliferator-activated receptor γ (PPAR-γ) agonists are used to treat type II diabetes and they have beneficial effects on inflammation, fibrosis, and angiogenesis. Hence, we evaluated the efficacy of the PPAR-γ agonist rosiglitazone (RSG) in ameliorating peritoneal membrane damage in a mouse PD model, and we analyzed the mechanisms underlying the protection offered by RSG. Exposure of the peritoneum to PD fluid resulted in AGEs accumulation, an inflammatory response, the loss of mesothelial cell monolayer and invasion of the compact zone by mesothelial cells, fibrosis, angiogenesis, and functional impairment of the peritoneum. Administration of RSG diminished the accumulation of AGEs, preserved the mesothelial monolayer, decreased the number of invading mesothelial cells, reduced fibrosis and angiogenesis, and improved peritoneal function. Interestingly, instead of reducing the leukocyte recruitment, RSG administration enhanced this process and specifically, the recruitment of CD3+ lymphocytes. Furthermore, RSG treatment augmented the levels of the anti-inflammatory cytokine interleukin (IL)-10 and increased the recruitment of CD4+ CD25+ FoxP3+ cells, suggesting that regulatory T cells mediated the protection of the peritoneal membrane. In cell-culture experiments, RSG did not prevent or reverse the mesothelial to mesenchymal transition, although it decreased mesothelial cells apoptosis. Accordingly, RSG appears to produce pleiotropic protective effects on the peritoneal membrane by reducing the accumulation of AGEs and inflammation, and by preserving the mesothelial cells monolayer, highlighting the potential of PPAR-γ activation to ameliorate peritoneal deterioration in PD patients.