The objective of this prospective clinical study was to evaluate the accuracy of pulse oximetry and capnography in healthy and compromised horses during general anesthesia with spontaneous and controlled ventilation. Horses anesthetized in a dorsal recumbency position for arthroscopy (n = 20) or colic surgery (n = 16) were instrumented with an earlobe probe from the pulse oximeter positioned on the tip of the tongue and a sample line inserted at the Y-piece for capnography. The horses were allowed to breathe spontaneously (SV) for the first 20 min after induction, and thereafter ventilation was controlled (IPPV). Arterial blood, for blood gas analysis, was drawn 20 min after induction and 20 min after IPPV was started. Relationships between oxygen saturation as determined by pulse oximetry (SpO2), arterial oxygen saturation (SaO2), arterial carbon dioxide partial pressure (PaCO2), and end tidal carbon dioxide (P(et)CO2), several physiological variables, and the accuracy of pulse oximetry and capnography, were evaluated by Bland–Altman or regression analysis. In the present study, both SpO2 and P(et)CO2 provided a relatively poor indication of SaO2 and PaCO2, respectively, in both healthy and compromised horses, especially during SV. A difference in heart rate obtained by pulse oximetry, ECG, or palpation is significantly correlated with any pulse oximeter inaccuracy. If blood gas analysis is not available, ventilation to P(et)CO2 of 35 to 45 mmHg should maintain the PaCO2 within a normal range. However, especially in compromised horses, it should never substitute blood gas analysis.