The purpose of this study was to test the hypothesis that the gastric ulcer medications, ranitidine and omeprazole, would alter plasma concentrations of total carbon dioxide (tCO2), lactate (LA), Na+, K+, Cl− and total protein (TP), as well as calculated plasma strong ion difference (SID) and packed cell volume (PCV) in horses subjected to a simulated race test (SRT). Twelve unfit Standardbred mares (~520 kg, 9–18 years) were used in a randomized crossover design with the investigators blind to the treatment given. Each mare received a treatment three times daily (TID) at 06.30, 12.30 and 18.30 hours. The treatments administered orally were omeprazole (4 mg kg− 1 was given in the morning with apple sauce given at the later, two dosing times to encourage good behaviour), ranitidine (6 mg kg− 1 crushed and mixed in 20 ml apple sauce) and control (20 ml apple sauce TID). Each horse completed a series of SRTs with blood samples taken via jugular venipuncture at five intervals (prior to receiving treatment, prior to SRT, immediately following exercise and at 60 and 90 min post-SRT). During the SRTs, each horse ran on a treadmill fixed on a 6% grade for 2 min at a warm-up speed (4 m s− 1) and then for 2 min at a velocity predetermined to produce VO2max. Each horse then walked at 4 m s− 1 for 2 min to complete the SRT. Plasma tCO2, electrolytes, LA and TP concentrations and PCV–TP were measured in duplicate at all intervals. No differences (P>0.05) were detected between control, ranitidine or omeprazole for any of the measured variables. There were differences (P < 0.05) in tCO2, SID, PCV, TP, LA and electrolyte concentrations relative to sampling time. However, these differences were attributable to the physiological pressures associated with acute exercise and not an effect of the medication. It was concluded that ranitidine or omeprazole did not alter plasma tCO2 concentration.