Fasting plasma amino acid levels were measured in 78 patients with chronic renal insufficiency (glomerular filtration rate [GFR], 8.0 to 56.0 mL/min), who had been enrolled in phase II of the Modification of Diet in Renal Disease study, prior to their beginning the experimental portion of the protocol. Alterations in many plasma amino acid levels were observed in the patients with the mildest degrees of renal insufficiency, and the number and severity of abnormalities tended to be greater in the patients with more severe renal failure. In patients with GFRs greater than 24.5 mL/min, 15 to 24.5 mL/min, and less than 15 mL/min, statistically significant abnormalities were observed in the concentrations or ratios of 9, 14, and 18 amino acids, respectively. The following correlations of amino acid levels or ratios with GFR were observed (all P < 0.001): citrulline, r = -0.41; citrulline to arginine ratio, r = -0.42; glycine to serine ratio, r = -0.37; N-tau methylhistidine, r = -0.65; and cystine, r = -0.37. Other weaker correlations observed were valine, r = 0.26 (P < 0.025); valine to glycine ratio, r = 0.32 (P = 0.004); and sum of isoleucine, leucine, and valine, r = 0.21 (P = 0.061). N-tau methylhistidine and the essential to nonessential amino acid ratio became altered with declining GFR in a nonlinear fashion. Thus, many of the characteristic alterations in the plasma amino acid profile that are observed in chronic end-stage renal disease are already present in mild renal insufficiency. Progressive loss of renal function generally results in increasing abnormalities; these changes in plasma amino acid concentrations with reduction in GFR were usually linear.