Many catabolic conditions are characterized by disturbances in acid-base balance and concomitant alterations in the insulin-like growth factor (IGF) system. However, the influence of acidosis per se on the various components of the IGF system has not been extensively examined. The purpose of the present study was to determine the effect of acute metabolic acidosis on the plasma and tissue concentrations of IGF-I and the various IGF-binding proteins (IGFBPs). Conscious unrestrained fasted rats were infused iv with either 0.2 N HCl or an equal volume of saline for 4 h. The arterial blood pH decreased within 60 min after starting the HCl infusion and remained lower than time-matched control values for the entire experimental protocol. Although the plasma IGF-I concentration fell gradually and was reduced by 30%, compared to time-matched control values, GH levels were unaltered. The IGF-I content of tissues collected at the conclusion of the experiment was increased in liver (35%) and kidney (63%), and unchanged in skeletal muscle. However, whereas acidosis moderately increased IGF-I messenger RNA abundance in liver, no significant alteration in IGF-I expression was detected in kidney. Acidosis also increased the plasma levels of IGFBP-1 and -2 as well as the IGFBP-1 content of liver and kidney. In contrast, the concentration of intact IGFBP-3 was decreased in acid-infused rats, and this reduction was associated with an increased rate of IGFBP-3 protease activity. Acidotic rats demonstrated unremarkable changes in the plasma concentrations of glucose and insulin, but corticosterone levels were elevated throughout the experiment. The results of the present study demonstrate that in the absence of underlying pathology, acute metabolic acidosis decreases circulating levels of IGF-I, probably by increasing renal clearance of the peptide, not by decreasing hepatic IGF-I synthesis.