In this review we summarize the findings from the literature and our own laboratory on the decreased PON1 activity in renal failure, the mechanisms proposed and the effect of interventions. In addition to profound alterations in lipoproteins, reduced serum PON1 activity has been clearly established in the past decade and could contribute to accelerated development of atherosclerosis in ESRD and in HD. PON1 lactonase activity is lower in ESRD patients. Hemodialysis partially restores PON1 lactonase and the other activities. PON1 activity recovery after dialysis suggests that uremic toxins may play a mechanistic role in PON1 inactivation. Lower PON1 activity in CRF patients is associated with low thiol concentration, high CRP, and is beneficially enhanced with vitamin C and flavonoids. Changes in HDL subclasses, namely lower HDL3in these patients may also play a role in PON1 lower activity. Future research should focus on: (1) mechanistic studies on causes for low PON1 activity and mass; (2) prospective studies focusing on whether there is an added predictive value in measuring PON1 activity (and PON1 activity in HDL3) in this patient population; (3) intervention studies attempting to increase PON1 activity.