Human serum paraoxonase is physically associated with an apolipoprotein (Apo-A1) and clusterin-containing high-density lipoprotein (HDL) and prevents low-density lipoprotein from lipid peroxidation. The aim of our study was to determine whether paraoxonase activity or phenotype is altered in patients with chronic renal failure and in hyperlipidemic subjects without renal insufficiency and to compare the values with those of healthy controls. We investigated the serum paraoxonase activity and polymorphism in 119 hemodialyzed uremic patients, 107 patients with primary hyperlipoproteinemia, and in 110 healthy control subjects. The serum paraoxonase activity was significantly decreased both in hyperlipidemic (p < 0.01) and uremic patients (p < 0.001) as compared with controls. On comparison, the serum paraoxonase activity was significantly lower (p < 0.001) in uremic than in hyperlipoproteinemic patients. The HDL and Apo-A1 levels were as follows: uremic < hyperlipidemic < control. To assess whether the observed reduction in paraoxonase activity was due to HDL and Apo-A1 level decreases, we standardized the enzyme activity for HDL and Apo-A1 concentrations. We found that the standardized paraoxonase activity (paraoxonase/HDL ratio) was also lower in the uremic patients (103.3 +/- 69.5) as compared with hyperlipidemic patients (137.64 +/- 81.0) and controls (194.45 +/- 94.45). The standardized values for Apo-A1 showed a similar tendency: paraoxonase/Apo-A1 ratio in uremic patients 89.64 +/- 47.8, in hyperlipidemic patients 128.12 +/- 69.83, and in controls 161.40 +/- 47.35. The phenotypic distribution of paraoxonase (AA, AB, BB) did not change significantly in the patient groups. These results suggest that HDL concentration and phenotypic distribution of paraoxonase may not be the only determining factors, but that other as yet undetermined factors could be involved in the enzyme activity changes.