This report describes the clinical and microbiological features of 30 refractory patients and their response to a combined local and systemic therapy at 6 weeks and 3 years following treatment. The refractory treatment protocol (RefTx) consisted of a 2-week regimen of amoxicillin/clavulanate potassium in conjunction with professional, intrasulcular delivery of povidone iodine, and chlorhexide mouthwash rinses b.i.d. Eighty-seven percent of the patients had favorable clinical responses to the RefTx and could be divided into 3 groups (A, B, C) based upon initial flora patterns and the shifts that occurred following treatment. Pretreatment prevalence of Porphyromonas gingivalis (P.g.) was 36.7%. The RefTx was effective in reducing P.g. below detection levels in 10 of the 11 positive patients at P < 0.01; each of these 10 patients (Group A) demonstrated significant gain in attachment. Other black-pigmented Bacteroides species (OBP) were isolated from 70% of the patients at baseline. Nine of these patients did not harbor P.g., showed clinical improvement upon treatment, and were OBP negative following treatment (Group B). Group C patients (7) demonstrated clinical improvement with therapy and did not fit into either Group A or B based upon microbial patterns. Group D patients (4) did not show clinical improvement with 3 patients harboring either P.g. or OBP after treatment. The RefTx was effective at reducing probing pocket depth with a 56% decrease in the number of pockets greater than 6 mm at 6 weeks. This was accompanied by an overall gain of > or = 1 mm of probable attachment in 45% of all sites. The clinical effects of the RefTx were shown to persist at 34.3 months with an apparent attachment gain of > or = 1 mm in 41.2% of sites. These data suggest that P.g. and OBP are important pathogens in refractory periodontitis and that the RefTx protocol is an acceptable, non-invasive alternative for the management of these patients.