The [H+] and [HCO3−] of biological solutions is determined by the [Formula: see text], the concentration of strong ions (mainly Na+, K+, Ca2+, Cl−, lactate−), and the concentration of weak acids (mainly proteins, phosphates). Two mathematical models are available that use a quantitative approach to describe the acid–base behaviour of plasma, but which differ in their treatment of the weak acid component: Stewart model (using [Formula: see text], strong ion difference (SID = [Na+ + K+ + Ca2+] − [Cl− + lactate−]) and [protein]TOT); Fencl model (using [Formula: see text], SID, [albumin], and [Pi]TOT). The present study compared measured and estimated [H+] and [HCO3−] in whole-blood samples collected from eight subjects during two double-ramp exercise protocols to the limit of tolerance to assess the accuracy with which each of the quantitative models predicts measured values. Arterialized-venous blood was analyzed for [H+], [Formula: see text], [protein]TOT, [albumin], [Pi]TOT, and SID (= [Na+ + K+ + Ca2+] − [Cl− + lactate−]), and these independent variables were then substituted into the appropriate mathematical model to estimate [H+] and [HCO3−]. Analysis showed that the [H+] and [HCO3−] estimated using either model provided a good estimate of the [H+] (Stewart model, r = 0.81; Fencl model, r = 0.81) and [HCO3−] (Stewart model, r = 0.93; Fencl model, r = 0.93) measured in plasma; linear regression analysis demonstrated that the slopes and intercepts for each of die relationships were not different (p > 0.05) from the line of identity. Differences between estimated and measured values were small, averaging < 3 nmol∙L−1 for [H+] and < 2 mmol∙L−1 for [HCO3−]. However, in the case of plasma [H+], the difference between estimated and measured values became skewed (i.e., [H+]M < [H+]Est) above [H+]M ≈ 55 nmol∙L−1, or at [SID] ≤ 35 mequiv.∙L−1. Reasons for the difference between measured and estimated values are discussed, with attention given to the [SID] and weak acid components.Key words: quantitative acid–base chemistry, strong ion difference, weak acids, strong ions, lactate, hydrogen ion, bicarbonate.