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OBJECTIVE To determine whether the partial pressure of end-tidal carbon dioxide (PetCO2 ) could predict return of spontaneous circulation (ROSC) in patients with cardiopulmonary arrest (CPA) undergoing CPR. DESIGN Prospective observational study. SETTING Two private specialty referral hospitals. ANIMALS Thirty-five client-owned dogs and cats in CPA in which CPR was performed and pertinent data recorded on a purpose-made form. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS PetCO2 was recorded at 1-minute intervals during CPR. Hospital, animal, arrest, and outcome variables were also reported in the Utstein style where possible. Twelve animals (7 dogs and 5 cats) achieved ROSC; 4 of these (2 dogs and 2 cats) had sustained ROSC, of which 1 dog was discharged alive. Patients that achieved ROSC had significantly higher initial PetCO2 (P = 0.0083), peak PetCO2 (P < 0.0001), average PetCO2 (P < 0.0001), and ΔPetCO2 (difference between last and first recorded PetCO2 ; P = 0.0004) than patients not resuscitated. The PetCO2 accurately discriminated between ROSC and failure to achieve ROSC at minutes 3, 4, 5, 6, 7, and 8 of CPR with area under the receiver operating characteristic curve of 0.926, 0.967, 0.938, 0.933, 0.956, and 1.00, respectively. The optimal cutoff PetCO2 was 18 mm Hg (2.4 kPa), with a sensitivity of ≥80% and a specificity of ≥95% at minutes 3, 4, 5, 6, and 8, correctly classifying 91-100% of cases. CONCLUSIONS The results of this small study support previous recommendations to monitor PetCO2 during CPR and suggest that PetCO2 during CPR may be useful for determining the probability of ROSC. Absolute values and trends of PetCO2 may assist clinicians and owners in making decisions for pets with CPA.