Abstract. Objective: Previous experiments in the authors swine lab have shown that cardiopulmonary resuscitation (CPR) using two-thumb chest compression with a thoracic squeeze (TT) produces higher blood and perfusion pressures when compared with the American Heart Association (AHA)-recommended two-finger (TF) technique. Previous studies were of short duration (1-2 minutes). The hypothesis was that TT would be superior to TF during prolonged CPR in an infant model. Methods: This was a prospective, randomized crossover experiment in a laboratory setting. Twenty-one AHA-certified rescuers performed basic CPR for two 10-minute periods, one with TT and the other with TF. Trials were separated by 2-14 days, and the order was randomly assigned. The experimental circuit consisted of a modified manikin with a fixed-volume arterial system attached to a neonatal monitor via an arterial pressure transducer. The arterial circuit was composed of a 50-mL bag of normal saline solution (air removed) attached to the manikin chest plate and connected to the transducer with a 20-gauge intravenous catheter and tubing. Rescuers were blinded to the arterial pressure tracing. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) were recorded in mm Hg, and pulse pressures (PPs) were calculated. Data were analyzed with two-way repeated-measures analysis of variance. Sphericity assumed modeling, with Greenhouse-Geisser and Huynh-Feldt adjustments, was applied. Results: Marginal means for TT SBP (68.9), DBP (17.6), MAP (35.3), and PP (51.4) were higher than for TF SBP (44.8), DBP (12.5), MAP (23.3), and PP (32.2). All four pressures were significantly different between the two techniques (p ≤ 0.001). Conclusion: In this infant CPR model, TT chest compression produced higher MAP, SBP, DBP, and PP when compared with TF chest compression during a clinically relevant duration of prolonged CPR.