BACKGROUND/OBJECTIVES: Metabolism is controlled by macro- and micronutrients. Protein-rich diets should lead to latent acidosis at tissue level with further negative implications. Food supplements with alkaline salts are available and popular pretending to prevent these changes. SUBJECTS/METHODS: Within a randomised double-blind placebo-controlled trial we tested the hypotheses that (1) a 4-week protein-rich diet induces a latent tissue acidosis and (2) an alkaline supplement can compensate this. Acid-base balance and important metabolic parameters were determined before and after 4 weeks of supplementation by peripheral blood samples, indirect calorimetry and muscle microdialysis before and after a protein-rich test meal. RESULTS: Fourty volunteers were randomised 1:1 to either verum or placebo supplements. Protein-rich diet by itself did not significantly affect acid-base balance. Alkaline supplementation increased plasma bicarbonate concentration without changing pH. Postprandial increases in serum glucose and insulin tended to be lower for verum vs. placebo. Resting and postprandial energy metabolism, and carbohydrate and fat oxidation did not differ significantly before and after supplementation in both groups. In muscle, postprandial glucose uptake and aerobic glucose oxidation were significantly higher for verum. In addition, verum significantly increased serum magnesium concentrations. CONCLUSIONS: Four weeks of protein-rich diet did not significantly influence acid-base balance. However, alkaline supplementation improved systemic and tissue acid-base parameters and oxidative glucose metabolism.