Chelation is usually considered to be the mechanism responsible for the decreased absorption of tetracycline in the presence of antacids containing polyvalent cations such as Ca++, Mg++, or Al+++. The present study shows that tetracycline absorption can also be reduced to a similar extent by sodium bicarbonate, an antaCid which contains no polyvalent cations and cannot form chelates with tetracycline. In a crossover study, 8 fasting subjects received a 250 mg. commercial tetracycline hydrochloride capsule and 200 ml. of water with or without 2.0 Gm. of sodium bicarbonate. Each subject receiving sodium bicarbonate showed a significant decrease in absorption. An average reduction in absorption of 50 per cent was observed as determined by the cumulative amount of unchanged tetracycline appearing in the urine at 48 hours (Qu∞). The mean Qu∞ was 114.1 ± 27.0 mg. for tetracycline alone and 52.5 ± 14.0 mg. when given with sodium bicarbonate. When tetracycline was dissolved prior to administration, no differences in Qu∞ were observed with or without concomitant administration of 2.0 Gm. of sodium bicarbonate, indicating that the dissolution rate step is involved in the decreased absorption of tetracycline capsules. These results are consistent with a mechanism of absorption requiring a low gastric pH for complete dissolution of tetracycline and suggest that any substance or condition which significantly increases gastric pH may decrease dissoltltion and, hence, absorption of tetracycline