The safety and efficacy of periodontal disease treatment by intrapocket placement of tetracycline (TC) fibers was investigated in a 60-day multicenter study conducted by selecting 4 sites in each subject with 6-10 mm pockets that bled on probing. Sites were randomly assigned to 1 of 4 test groups: TC fiber therapy, scaling, control fiber (fibers without drug), or untreated. TC fibers and control fibers were placed to fill the pocket and were maintained with a cyanoacrylate adhesive for 10(+/- 2) d. Scaling was performed for a minimum of 5 min under local anesthesia. Following initial tooth cleaning procedures, pocket depth, attachment level and bleeding on controlled-force probing were measured at baseline and at 30 d, and 60 d following therapy. Analysis of data from 107 subjects who had complete clinical data sets indicated that TC fiber therapy significantly decreased pocket depth, increased attachment level, and decreased bleeding on controlled-force probing to a greater extent than observed in all other test groups including scaling. These effects were greater than, and in addition to, effects that occurred due to prophylaxis and improved home care. No serious adverse side-effects attributed to TC fiber therapy were observed. No TC fiber-treated sites abscessed and superinfection was not noted. A transient redness at fiber removal was seen at 21% of the sites. Although fibers were placed without anesthesia, mild pain on initial placement was infrequent (19%) and abated rapidly. The results indicate that TC fiber placement provides a safe and effective means for treatment of periodontal infections.