S-Adenosylhomocysteine (SAH) is the metabolic precursor of all the homocysteine (Hcy) produced in the body. It is formed by the enzyme SAH hydrolase in a reversible reaction. In a previous study we have shown that plasma SAH is a more sensitive indicator of the risk for cardiovascular disease, and in a second study involving patients with renal disease, we also showed that it is a more sensitive indicator of renal insufficiency than plasma Hcy. However, in the latter study, the patients with renal disease were older and had a variety of other diseases such as diabetes and primary hypertension, which are associated with vascular disease and which could reduce renal function by involvement of the kidneys. Our objective was to rule out these complicating factors as the cause of the elevated SAH in renal disease and determine whether renal insufficiency alone was the cause of the elevated SAH. We therefore measured SAH, Hcy, folate, and vitamin B12 in 23 patients between the ages of 1 and 18 years with a wide range of renal function, but who had none of these complicating factors. Glomerular filtration rate (GFR) was calculated using serum creatinine according to the Schwartz formula. None of the children were deficient in folate or vitamin B12. After adjusting for age, folate, and vitamin B12, there was a modest and insignificant decrease of 0.033 micromol/L of Hcy associated with an increase of 1 mL/min of GFR (95% confidence interval, -0.066 to 0.0002). However, there was a strong and statistically significant association between log(SAH) and log(GFR): P < .0005, R2 = 0.76. This result suggests that plasma SAH rather than Hcy is the metabolite primarily affected in renal disease. We suggest that plasma Hcy elevations that have been linked to vascular disease may be due to elevated SAH resulting from renal insufficiency.