Background: Hypoxia occurs during one-lung ventilation (OLV) due to the arteriovenous shunt of unsaturated pulmonary venous blood. Hypoxic pulmonary vasoconstriction (HPV) acts as a defense mechanism against shunting. In thoracic surgery, anesthetics with minimal inhibitory effect on HPV and minimal hemodynamic changes are preferred. Objectives: The present study aimed to evaluate the effects of propofol and isoflurane on patients’ arterial oxygen pressure following onelung ventilation during thoracic surgeries. Materials and Methods: In this randomized clinical trial study which was conducted in Iran, sixty patients with ASA (The American Society of Anesthesiologists) class I & II who were candidates for right elective thoracotomy were divided in two groups. Induction of anesthesia in the two groups was conducted using the same method, and left double-lumen endotracheal tube was inserted. In the first group propofol was used for the maintenance of anesthesia, and isoflurane for the second group. During two-lung ventilation and at minutes 5 and 10 after OLV, ABG (arterial blood gas) (for detecting the mean pressure of arterial oxygen), mean arterial pressure and heart rate were recorded. Results: Sixty patients (mean age = 4124.18 ± 18.63 years) were divided into two groups. The age and gender of the subjects were not statistically different between the two groups. In the propofol group, the arterial oxygen pressure during two-lung ventilation and at 5th and 10th minutes after OLV was 263.14 ± 136.19, 217.40 ± 133.99 and 182.34 ± 122.39; in the isoflurane group, it was reported as 206.29 ± 135.59, 164.78 ± 118.90 and 155.35 ± 109.21 mmHg, respectively. In the propofol group, mean arterial pressure during two-lung ventilation, and 5th and 10th minutes after OLV, was 84.01 ± 20.67, 88.15 ± 20.23 and 86.10 ± 19.13, respectively; regarding the isoflurane group, it was reported as 79.66 ± 17.04, 84.78 ± 20.19 and 86.50 ± 17.07 mmHg, respectively. In the propofol group, heart rate during two-lung ventilation, and 5th and 10th minutes after OLV was 92.77 ± 17.20, 94.0 ± 18.34 and 94.33 ± 21.03, respectively; In the isoflurane group, it was reported as 92.87 ± 16.96, 91.8 ± 18.75 and 91.05 ± 17.20 min, respectively. These values were statistically similar in the two study groups. Conclusions: The effects of propofol on hemodynamics and arterial oxygen pressure during one- or two-lung ventilation were not different from those of isoflurane.