In 64 apparently healthy adult humans (ages 17-74 yr) ingesting controlled diets, we investigated the separate and combined effects of age, glomerular filtration rate (GFR, index of age-related renal functional decline), renal net acid excretion [NAE, index of endogenous acid production (EAP)], and blood PCO2 (PbCO2, index of respiratory set point) on steady-state blood hydrogen ion ([H+]b) and plasma bicarbonate concentration ([HCO3-]p). Independent predictors of [H+]b and [HCO3-]p were PbCO2, NAE, and either age or GFR, but not both, because the two were highly correlated (inversely). [H+]b increased with increasing PbCO2, NAE, and age and with decreasing GFR. [HCO3-]p decreased with increasing NAE and age but increased with increasing PbCO2 and GFR. Age (or GFR) at constant NAE had greater effect on both [H+]b and [HCO3-]p than did NAE at constant age (or GFR). Neither PbCO2 nor NAE correlated with age or GFR. Thus two metabolic factors, diet-dependent EAP and age (or GFR), operate independently to determine blood acid-base composition in adult humans. Otherwise healthy adults manifest a low-grade diet-dependent metabolic acidosis, the severity of which increases with age at constant EAP, apparently due in part to the normal age-related decline of renal function.