The objective of this study was to compare the efficacy of a systemic antibiotic (doxycycline) and a non-steroidal anti-inflammatory drug (ibuprofen), administered either separately or combined, as an adjunctive treatment of scaling/root planing (SRP). Thirty-two subjects diagnosed with generalized moderate adult periodontitis and having at least 2 teeth with > or =5 mm probing depth were randomly divided into 4 groups. Each group was treated with oral doxycycline and/or ibuprofen for 6 weeks as follows: group 1, doxycycline 200 mg the first day followed by 100 mg per day; group 2, ibuprofen 800 mg per day; group 3, doxycycline plus ibuprofen scheduled as in groups 1 and 2; group 4, one placebo capsule/day (control). A split mouth design was utilized in each subject such that half of the teeth received one session of scaling/root planing (SRP), while the other half received no SRP. Plaque index (PI), gingival index (GI), probing depth (PD), and clinical attachment level (CAL) using a customized acrylic stent were recorded at baseline and at 3, 6, 12, and 24 weeks following SRP. Analysis using ANOVA and Student t-test showed statistical significance (P< or =0.05) from baseline data in: 1) gains of 0.4 mm and 0.5 mm of CAL for groups 1 and 3, respectively; 2) reduction of 0.7 mm PD for group 3; 3) reduction of 0.4 and 0.1 GI scores for groups 1 and 3, respectively; and 4) gain of 0.5 mm CAL and reductions of 0.4 mm PD and 0.2 GI score for the SRP group when compared to the no SRP group at 24 weeks. It may be concluded that the adjunctive use of systemic doxycycline alone or in combination with ibuprofen results in a statistically significant, yet modest clinical, improvement beyond that obtained by scaling/root planing.