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Background: The objective of this double-masked, randomized, multicenter crossover study was to compare the efficacy of 4% articaine HCl with 1:100,000 epinephrine (A100) to 4% articaine HCl with 1:200,000 epinephrine (A200) for providing effective local anesthesia and hemostasis for periodontal surgery. Methods: Anesthetic efficacy was based on patient self-report and lack of need for reinjection during the surgical procedures. Hemostatic properties of the formulations were compared using ratings of the surgeons' ability to visualize the surgical field and expectation for bleeding. The volume of blood collected during each surgical session also was measured and compared. Results: Forty two adult subjects (26 males and 16 females, mean age 46.3 ± 9.7 years) diagnosed with moderate to severe periodontal disease requiring local anesthesia for matched bilateral periodontal surgery were enrolled and completed the study. Subjects reported satisfactory surgical anesthesia following the A100 and A200 formulations; no supplemental local anesthesia was administered. Significant differences between the A100 and A200 treatments were found for the surgeons' ability to visualize the surgical field (rated as clear 83.3% of the time with A100 and 59.5% of the time with A200; P 0.008), bleeding expectation (rated as equal to or better than expected 85.7% of the time with A10g and 71.4% of the time with A200; P 0.034), and volume of blood loss (54.9 ± 36.0 ml for A100 and 70.2 ± 53.0 ml for A200; P = 0,018). Sixteen patients experienced 27 mild or moderate adverse events; the most common were postoperative pain (nine patients) and swelling (eight patients). Six adverse events may have been related to treatment. The frequency of adverse events did not vary between formulations. Conclusions: For patients undergoing periodontal surgery, 4% articaine anesthetic formulations containing epinephrine (1:100,000 or 1:200,000) provided excellent surgical pain control. For patients who can tolerate higher amounts of epinephrine, the 4% articaine 1:100,000 epinephrine formulation had the additional therapeutic advantage of providing better visualization of the surgical field and less bleeding. J Periodontol 2007;78:247-253. [ABSTRACT FROM AUTHOR]