BACKGROUND This randomized controlled clinical trial was designed to compare the clinical outcomes of guided tissue regeneration with calcium sulfate graft and membrane (CS) versus guided tissue regeneration with collagen membrane (CM) or open flap debridement (OFD) only in terms of clinical attachment gain in periodontal intrabony defects. METHODS Fifty-one systemically healthy, non-smoking subjects affected by moderate to severe chronic periodontitis were recruited. The subjects had one deep intrabony defect with a probing depth (PD) > or =6 mm and were randomly divided into three equal groups (17 subjects per group). Subjects were surgically treated with OFD (OFD group), OFD with CS (CS group), or OFD and CM (CM group). One year after surgical treatment, a complete clinical examination and a surgical reentry were performed. The pre- and post-therapy clinical parameters, including PD, clinical attachment level (CAL), gingival recession (GR), and intrasurgical parameters (defect bone level [DBL]), were compared. RESULTS After 1 year, the clinical and intrasurgical parameters showed statistically significant changes from baseline within each group for all of the evaluated parameters (PD and CAL, P <0.001; GR and DBL, P <0.05). Differences (PD, CAL, and DBL, P <0.001; GR, P <0.05) were also seen across the three groups. The CM and CS groups had significantly smaller PD, CAL, and DBL values than subjects treated with only OFD. Groups treated with regenerative techniques had a significantly greater PD reduction and CAL and DBL gain compared to the OFD group. No significant differences were seen between CM and CS. Conversely, the CM group showed a significantly greater GR increase compared to OFD and CS. CONCLUSIONS Both regenerative treatments produced additional clinical benefits over OFD alone. Moreover, the use of CS may minimize post-surgical recession.