This double-blind crossover "split-mouth" trial evaluated the cardiovascular effects induced by 3.6 mL of the LA 2% HCl mepivacaine with 1:100,000 epinephrine, concomitantly with 75 TRU/mL hyaluronidase or placebo in inferior alveolar nerve block, for the performance of bilateral and symmetrical third molar surgery in 20 outpatients. Cardiovascular parameters, including systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR), were monitored using oscillometric and photoplethysmographic methods in 10 clinical stages. Electrocardiographic records (ECG) of 12 leads were obtained in four steps. Hyaluronidase injected concomitantly with LA did not induce changes in SBP, DBP and HR compared to placebo. There were no instances of ST segment depression, ST segment elevation, wide QRS complex extrasystoles, or narrow QRS complex extrasystoles.