Simple and accurate expressions describing the PO-FO relationship in mechanically ventilated patients are lacking. The current study aims to validate a novel mathematical expression for accurate prediction of the fraction of inspired oxygen that will result in a targeted arterial oxygen tension in non-smoking and smoking patients receiving mechanical ventilation following open heart surgeries. One hundred PO-FO data pairs were obtained from 25 non-smoking patients mechanically ventilated following open heart surgeries. One data pair was collected at each of FO of 40, 60, 80, and 100% while maintaining same mechanical ventilation support settings. Similarly, another 100 hundred PO-FO data pairs were obtained from 25 smoking patients mechanically ventilated following open heart surgeries. The utility of the new mathematical expression in accurately describing the PO-FO relationship in these patients was assessed by the regression and Bland-Altman analyses. Significant correlations were seen between the true and estimated FO values in non-smoking (r = 0.9424; p < 0.05) and smoking (r = 0.9466; p < 0.05) patients. Tight biases between the true and estimated FO values for non-smoking (3.1%) and smoking (4.1%) patients were observed. Also, significant correlations were seen between the true and estimated PO/FO ratios in non-smoking (r = 0.9530; p < 0.05) and smoking (r = 0.9675; p < 0.05) patients. Tight biases between the true and estimated PO/FO ratios for non-smoking (-18 mmHg) and smoking (-16 mmHg) patients were also observed. The new mathematical expression for the description of the PO-FO relationship is valid and accurate in non-smoking and smoking patients who are receiving mechanical ventilation for post cardiac surgery.