The aim of the present study was to test whether or not the application of an in situ formed synthetic hydrogel made of polyethylene glycol (PEG) used as a biodegradable membrane for guided bone regeneration will result in the same amount of bone regeneration as with the use of an expanded polytetrafluoro-ethylene (ePTFE) membrane. In eight New Zealand White rabbits, four evenly distributed 6 mm diameter defects were drilled into the calvarial bone. Three treatment modalities were evenly distributed among the 32 defects: hydroxyapatite (HA)/tricalciumphosphate (TCP) granules covered at the outer and inner surface with a PEG membrane (test), HA/TCP granules covered at the outer and inner surface with an ePTFE membrane (positive control) and HA/TCP granules alone without membranes (negative control). After 4 weeks, the animals were sacrificed and the calvarial bones were removed. The area fraction of newly formed bone was determined by histomorphometrical analysis of the vertical sections from the middle of the defect and by micro-computed tomography of the entire defect. Multiple regression analysis (SAS® GLM) was used to model the amount of new bone formation. The quantitative histomorphometric analysis clearly revealed higher values of newly formed bone for the two membrane groups compared with the negative control group. The average area fractions of newly formed bone measured within the former defect amounted to 20.3±9.5% for the PEG membrane, 18.9±9.9% for the ePTFE membrane, and 7.3±5.3% for the sites with no membrane. The micro-computed tomography also showed higher values of new bone formation for the PEG and for the ePTFE groups compared with the negative control group. The GLM revealed a highly significant effect of the treatment on the amount of bone formation (P=0.0048). The values for the negative control group were significantly lower than the ones found in the PEG membrane group (P=0.0017), whereas the ePTFE membrane group showed no significant difference from the PEG membrane group. It is concluded that the PEG membrane can be used successfully as a biodegradable barrier membrane in the treatment of non-critical-size defects in the rabbit skull, and leads to similar amounts of bone regeneration as an ePTFE membrane.