THE PURPOSE OF THE PRESENT STUDY WAS TO EVALUATE the effect of anti-infective therapy on the success of periodontal regeneration in mandibular Class II furcation defects. Eighteen patients with mandibular bilateral Class II furcation defects were enrolled. Following an initial hygienic phase, guided tissue regeneration (GTR) was performed using an expanded polytetrafluoroethylene (e-PTFE) membrane barrier. The area was surgically exposed, thoroughly root planed, and irrigated with either tetracycline (100 mg/ml) or 0.9% saline. Post-operative care included systemic tetracycline (250 mg q.i.d.) and chlorhexidine 0.12% mouthwash twice daily. Patients were maintained on a prophylaxis schedule of every 2 weeks for the first 3 months, and monthly thereafter. Clinical parameters of probing depth (PD), probing attachment level - vertical (PAL-v), probing attachment level - horizontal (PAL-h), and target periodontal pathogens were monitored at baseline and quarterly for one year. An overall improvement in all clinical parameters was observed in both groups: probing reduction (3.1 mm), PAL-h gain (2.3 mm), and PAL-v gain (1.2 mm) were all statistically significant compared to baseline measurements. Vertical measurements were performed parallel to the long axis of the tooth with no attempt to angulate the probe into the furcation. There was no significant difference in sites receiving tetracycline. A strong positive correlation was noted between initial PD and pocket reduction (r = 0.77, P <0.0001) and between initial PD and PAL-h gain (r = 0.54) and PAL-v gain (r = 0.45) suggesting that initial probing depth might be used to assess the regenerative potential of a given site. PD and PAL have shown marked improvement as early as 6 months post-operatively, but further improvement occurred over the 12 months of the study. Mean plaque indices were reduced to 0.5 with slight increases at 9 months, while gingival indices were steady at 0.5 through the year. Immunofluorescence demonstrated minimal infection with the target periodontal pathogens following surgery. Actinobacillus actinomycetemcomitans was detected in 5 sites during the monitoring phase and was associated with less favorable clinical results. This finding suggests that anti-infective therapy and monitoring for A. actinomycetemcomitans and/or other periodontal pathogens might be useful in GTR therapy.