Introduction Acid-base disorders are associated with many diseases of the critically ill patient. Early treatment with sodium bicarbonate of these metabolic disorders is required for their normalization. This is an alkaline electrolyte solution administered by continuous or intermittent infusion. Its incompatibility due to its alkaline pH has been described, as it produces insoluble carbonate precipitation and causes carbon dioxide gas when mixed with acidic solutions. Material and method An in vitro experimental study was performed. Bicarbonate was mixed with 13 drugs simulating Y-site administration. We combined 5 ml bicarbonate with 5 ml of every drug, at highest daily concentration used. The samples were visually examined to detect color changes, cloudiness, precipitation or gas formation, pH measurement and spectrophotometric analysis at 450 nm and 620 nm. The samples were evaluated at 0, 15, 30, 60 and 120 minutes. The compatibility criteria were absence of visual changes, pH changes < 0.5 and variability of absorbance <0.01. Results We studied each drug individually and mixed with bicarbonate with 27 samples, and 135 measurements were performed. The incompatibilities did not always produce visual changes. Knowing the pH of drugs does not guarantee the compatibility of the mixture. Nitroglycerin with pH 4 is compatible with bicarbonate. Thiopental with pH 11 makes precipitation. Higher absorbances showed color changes, cloudiness and precipitation. Conclusions Bicarbonate is physically compatible with esmolol, furosemide, heparin, insulin, morphine, nimodipine, nitroglycerin and urapidil and incompatible with amiodarone, cisatracurium, haloperidol, midazolam and thiopental.