ABSTRACT Longitudinal evolution of peritoneal protein loss (PPL), a reflection of hydrostatic pressure–driven leak of plasma proteins through the large‐pore pathway, is not clear. Time on PD causes loss of mesothelial cells, vasculopathy, and increased thickness of the submesothelial fibrous layer. Are these structural changes associated with progressive increase of PPL, in a parallel with the rise in the D/P creatinine? The aim of the present study was to identify longitudinal changes of PPL over time. This single‐center, longitudinal study included 52 peritoneal dialysis (PD) patients with a median follow‐up of 26.5 months, evaluated at two different time points with a minimum interval of 6 months. Repeated measures analysis was performed using paired sample t ‐test or the nonparametric Wilcoxon signed‐rank test, depending on the distribution. After a median interval of 15.5 months, lower levels of residual renal function and urine volume, lower Kt/V, and creatinine clearance were found. D/P creatinine and PPL were stable, but a decrease in ultrafiltration was present. Systemic inflammation, nutrition, and volume overload showed no significant change with time on PD. Analysis of a subpopulation with over 48 months between initial and subsequential assessment ( n = 11) showed again no difference in inflammation, nutritional and hydration parameters from baseline, but importantly PPL decreased after more than 4 years on PD (mean difference 1.2 g/24, p = 0.033). D/P creatinine and dip of sodium remained unchanged. The absence of deleterious effects of time on PD is reassuring, pointing to the benefit of updated PD prescription, including the standard use of more biocompatible solutions towards membrane preservation and adjusted prescription avoiding overhydration and inflammation while maintaining nutritional status. After controlling for confounders, PPL may act as a biomarker of acquired venous vasculopathy, even if small pore fluid transport rates and free water transport are preserved.