Background Long-term peritoneal dialysis (PD) requires that the peritoneal membrane remain effective for dialysis. Research directed toward human peritoneal morphology and structure is limited. The present study was performed to investigate morphological changes of the human peritoneal membrane during PD and to elucidate the possible mechanisms of its functional deterioration. Methods A total of 32 peritoneal biopsies were performed in normal subjects (n=10), uremic nondialysis patients (n=12) at the time of catheter insertion, and PD patients (n=10) at the time of catheter removal or reinsertion or at the time of renal transplantation. Peritoneal morphology was examined by light microscopy, scanning electron microscopy, and transmission electron microscopy. Results The peritoneal membrane in normal subjects consisted of a monolayer of mesothelial cells on a basement membrane and a layer of connective tissue containing cells, blood vessels, and lymphatic vessels. Mesothelial cells were polygonal, often elongated, and had numerous microvilli on their luminal surface. There were lots of oval or roundish pinocytotic vesicles in the cytoplasm of the mesothelial cells. The peritoneal morphology of uremic nondialysis patients was similar to that of normal subjects. However, significant abnormalities of the peritoneal membrane were observed in PD patients, and the changes were found to be progressive. Microvilli were the first site of damage which involved microvilli shortening, a gradual reduction in their number, and, eventually, the total disappearance of microvilli. Mesothelial cells then detached from the basement membrane, disappearing completely in some cases. In the end, the peritoneal membrane consisted only of submesothelial connective tissue without any cells.Conclusions PD can modify peritoneal morphology and structure. The morphological change is progressive and may be one of the important causes of peritoneal failure. Peritoneal biopsies can provide lots of valuable information about the effects of PD. Studying the relationship between peritoneal structure and its function proved very useful for understanding the physiopathology of the peritoneum during PD.