There is a linear relationship between the PaCO2 and blood hydrogen ion concentration in normal dogs, but for theoretical reasons to be discussed, we questioned whether this relationship would apply in animals with metabolic acidosis or alkalosis. To study this in more detail, animals were divided into three groups: normal, metabolically acidotic, and metabolically alkalotic. Following anesthesia and bilateral ureteral ligation, dogs were intubated and ventilated to produce acute steady state PaCO2 values corresponding to the range observed during disease states. Changes in the volume and electrolyte composition of the gastrointestinal fluid and urine as well as the concentration and distribution of lactate were evaluated in all experiments. We observed the previously described linear relationship between the PaCO2 and blood hydrogen ion concentration in normal dogs, but the slope of the regression line differed significantly from those of dogs with metabolic acidosis and metabolic alkalosis. On the other hand, there was a consistent relationship between the ratio of the PaCO2 values, but not the absolute PaCO2, and the change in the plasma bicarbonate concentration over a wide range of PaCO2 values in all groups of dogs. The chemical basis for these observations will be discussed.