Objectives To investigate the degree and the determinants of peritoneal homocysteine (Hcy) clearance and to compare measured Hcy clearance with the Hcy clearance predicted based on molecular weight (MW). Design Cross-sectional observational analysis. Setting Tertiary care institutional dialysis center. Patients Sixty-five stable peritoneal dialysis (PD) patients. Outcome Measures Fasting blood and 24-hour pooled dialysate effluents were collected for determination of peritoneal clearances of Hcy (CpHcy), urea (CpUr), and creatinine (CpCr). The dialysate-to-plasma creatinine ratio at 4 hours (D/P Cr 4 h) and levels of red cell folate, B₁₂, ferritin, and C-reactive protein (CRP) were measured concurrently. Observed CpHcy was compared with predicted clearance, based on Hcy plasma protein binding and the relative molecular weights of Hcy, urea, and creatinine. Results Plasma concentrations of Hcy averaged 24.6 ± 1.1 μmol/L and were elevated above the upper limit of normal in 59 (91%) patients. The mean dialysate concentration of Hcy was 2.9 ± 0.3 μmol/L, equating to a daily peritoneal elimination of 34.6 ± 3.6 μmol. Observed CpHcy was closely approximated by predicted CpHcy (8.7 ± 0.6 L/week/1.73 m² vs 9.0 ± 0.3 L/week/1.73 m² respectively, p = 0.55). Patients maintained on automated PD ( n = 5) had a CpHcy similar to that of patients treated with continuous ambulatory peritoneal dialysis (8.9 ± 1.0 L/week/1.73 m² vs 8.7 ± 0.6 L/week/1.73 m², p = 0.92). The CpHcy was significantly correlated with C-reactive protein (CRP), D/P creatinine, CpUr, CpCr, and peritoneal protein loss, but not with plasma Hcy, albumin, B₁₂, ferritin, age, dialysis duration, peritonitis episodes, or daily dialysate effluent volume. By multivariate analysis, the only variables that remained significant independent predictors of CpHcy were CRP and D/P Cr 4 h. High and high-average transporters had a higher CpHcy than low and low-average transporters (9.7 ± 0.8 L/week/1.73 m² vs 7.0 ± 0.7 L/week/1.73 m², p < 0.05), despite comparably elevated plasma Hcy concentrations [25.2 ± 1.5 μmol/L vs 23.4 ± 1.6 μmol/L, p = nonsignificant (NS)]. Conclusions Elevated plasma concentrations of Hcy are not efficiently reduced by PD. The relatively low peritoneal clearance of Hcy is largely accounted for by a high degree of plasma protein binding and is significantly influenced by peritoneal membrane permeability.