Objective To evaluate the safety, efficacy, and biocompatibility of icodextrin and glucose-containing dialysis fluid during continuous cycling peritoneal dialysis (CCPD), patients were treated for 2 years with either icodextrin or glucose-containing dialysis fluid for their daytime dwell (14 -15 hours). Prior to entry into the study, all patients used a standard glucose solution (Dianeal 1.36%,2.27%, or 3.86%, Baxter, Utrecht, The Netherlands). Design Open, randomized, prospective, two-center study. Setting University hospital and teaching hospital. Patients Both established and patients new to CCPD were included. A life expectancy of more than 2 years, a stable clinical condition, and written informed consent were necessary before entry. Patients aged under 18, those with peritonitis in the previous month, and women of childbearing potential, unless taking adequate contraceptive precautions, were excluded. Thirty-eight patients entered the study, and 25 (13 glucose, 12 icodextrin) had a follow-up period of 12 months or longer in December 1996. Main Outcome Measures Serum icodextrin metabolites: one to five glucose units (G1–G5), a high molecular weight fraction (G > 10), and total carbohydrate level, as well as a biochemical profile were determined every 3 months in combination with all other study variables. Results In icodextrin-treated patients, serum disaccharide (maltose) concentrations increased from 0.05 ± 0.01 (mean±SEM) at baseline, to an average concentration in the follow-up visits of 1.14 ± 0.13 mg/mL (p < 0.001). All icodextrin metabolites increased significantly from baseline, as illustrated by the serum total carbohydrate minus glucose levels: from 0.42 ± 0.05 mg/mL to an average concentration in the follow-up visits of 5.04 ± 0.49 mg/mL (p < 0.001). At the same time, serum sodium levels decreased from 138.1 ± 0.7 mmol/L to an average concentration in the follow-up visits of 135.4 ± 0.8 mmol/L (p < 0.05). However, after 12 months the serum sodium concentration increased nonsignificantly (NS) from base line to 136.6 ± 0.9 mmol/L, after an initial decrease. Serum osmolality increased significantly from baseline in icodextrin users at 9 and 12 months, but did not differ significantly from glucose users in any visit. In icodextrintreated patients, the calculated serum osmolal gap increased significantly from 4.1 ± 1.4 mOsm/kg to an average of 11.8 ± 1.7 mOsm/kg (p < 0.01). The sum of the serum icodextrin metabolites in millimoles/liter equaled the increase in osmolal gap. Body weight increased in icodextrin users (71.9 ± 2.7 kg to 77.8 ± 3.0 kg; NS). Clinical adverse effects did not accompany these findings. Residual renal function remained stable during follow-up. Conclusions The serum icodextrin metabolite levels in the present study increased markedly and were the same as those found previously in continuous ambulatory peritoneal dialysis patients treated with icodextrin, despite thelonger dwell time for CCPDpatients (14 -16 hr versus 8 -12 hr). The initial decrease in serum sodium concentration was followed by an increase to a concentration not different from baseline at 12 months. The pathophysiology of this finding is speculated. Calculated osmolal gap in icodextrin patients increased significantly (p < 0.01) at every follow-up visit, and could be explained by the serum icodextrin metabolite increase. We encountered no clinical side effects of the observed levels of icodextrin metabolites.