Increased production of organic acid can result in an elevated serum anion gap and may play a role in the development of hypertension. We studied the cross-sectional associations between anion gap and blood pressure and between serum bicarbonate and blood pressure in the 1999-2000 and 2001-2002 National Health and Nutrition Examination Surveys. We included 5043 adult participants who were not taking antihypertensive medications or diuretics and who denied hypertension, cardiovascular disease, diabetes, and other diseases. Linear regression was used to adjust for age, race, body mass index, creatinine, albumin, and other factors. Sample weights were used to produce weighted regression parameters. In the lowest quintile of anion gap, mean values of sodium, chloride, and bicarbonate were 139 mEq/L, 105 mEq/L, and 25 mEq/L, respectively. In the highest quintile, mean values of sodium, chloride, and bicarbonate were 140 mEq/L, 101 mEq/L, and 22 mEq/L, respectively. Mean blood pressure was 118/72 mm Hg. After multivariable adjustment, participants in the highest quintile of anion gap had systolic blood pressure 3.73 mm Hg higher (95% CI: 1.83 to 5.63 mm Hg; P for trend: <0.01) than participants in the lowest quintile. Participants in the highest quintile of bicarbonate had systolic blood pressure 2.73 mm Hg lower (95% CI: 1.26 to 4.20 mm Hg; P for trend: <0.01) than participants in the lowest quintile. No associations were observed between anion gap or bicarbonate and diastolic blood pressure. The results were unchanged after excluding participants with estimated glomerular filtration rate <60 cc/min per 1.73 m(2). The anion gap is independently associated with higher blood pressure. Further research is needed to elucidate the relation between organic acid and hypertension.