15 adults, each providing 4 non-adjacent untreated periodontal pockets with a probing depth (PD) exceeding 6 mm, volunteered for a randomized, split-mouth, double-blind, clinical study evaluating subgingival irrigation with chlorhexidine (CHX) or tetracycline HCl (TTC). The study protocol included oral hygiene instructions followed by scaling and root planing. Experimental and immediately adjacent teeth did not receive instrumentation. The 4 deep periodontal pockets in each patient were assigned to be irrigated with 150 ml CHX (0.12%), TTC (10 or 50 mg/ml; TTC10, TTC50), or sterile saline (control) in a single episode. Post-irrigation mechanical plaque control was supported by 2x daily CHX rinses throughout the 12-week observation interval. Recordings of oral hygiene (P1I), gingival health (GI), bleeding on probing (BoP), probing depth (PD), clinical attachment level (CAL), and microbial morphotypes from subgingival paper point samples were performed pre-irrigation, and at 1, 2, 4, 6, 8, 10, and 12 weeks post-irrigation. Mean post-irrigation P1I was low, fluctuating between 0.0 and 0.4, without significant differences between experimental groups. Mean pre-irrigation GI approximated 1.4 and reached 0.8 at the exit of study without significant differences between experimental groups. All experimental sites exhibited BoP pre-irrigation. BoP was significantly reduced in TTC50 compared to TTC10, CHX and control sites from week 8 post-irrigation. PDs were reduced for the experimental groups with TTC50 exhibiting the strongest reduction. CALs remained unaltered from pre-irrigation for TTC10, CHX and control sites over the 12-week observation interval, whereas TTC50 sites consistently improved to significantly differ from all other groups at week 10 and 12 post-irrigation. The distribution of bacterial morphotypes was significantly altered towards one of periodontal health for all experimental groups with a profound effect for TTC50 sites. Our results suggest that subgingival irrigation with TTC solutions at high concentrations may have a role in the management of adult periodontitis.