By means of a pistol-grip syringe, 0.3 ml. of normal saline solution, 2 percent lidocaine with and without 1:100,000 epinephrine, 3 percent mepivicaine, and 1:100,000 epinephrine alone were injected into large adult dogs via the intravenous, intraosseous, intrapulpal, subcutaneous, periodontal, intramuscular, and submucosal, routes. Changes in heart rate, blood pressure, and respiration were recorded in relation to the time of injection. In the quantities injected, normal saline solution, 2 percent lidocaine, and 3 percent mepivicaine had no measurable effect on the systemic parameters, regardless of the site of injection. Injection of 2 percent lidocaine with epinephrine and of epinephrine alone caused transient decreases in blood pressure and increases in heart rate. The results were similar, whether the injections were done intravenously, intraosseously, or periodontally. Systemic changes were not detected when the epinephrine-containing agents were injected intramuscularly, subcutaneously, submucosally, or intrapulpally. These results support the contention that the periodontal injection is intraosseous in nature and that solutions injected by the periodontal technique are rapidly absorbed into the systemic circulation.