Serum paraoxonase (PON1) is an enzyme associated exclusively with high-density lipoproteins and seems to be an antiatherogenic agent that prevents initiation and progression of atherosclerosis. PON1 also hydrolyzes organophosphates, protecting the nervous system from those neurotoxic compounds. Furthermore, PON1 could be a potential indicator for predicting and preventing other diseases, such as coronary artery disease, different kinds of cancers, diabetes mellitus type 2, metabolic syndrome, neurological disorders, liver disorders, etc. Here we report an ultrasensitive assay to measure PON1 arylesterase activity relying on the enzymatic modulation of the growth of fluorescent CdS nanoparticles (NP). The lowest PON1 activity that could be detected by our system was 0.625 mU mL(-1), with a dynamic range up to 5 mU mL(-1). This new system leads to an improvement of the limit of detection by around 15 times, compared to the conventional assays to determine PON1 arylesterase activity. This new system was also applied to determine PON1 arylesterase activity in human serum by the standard addition method. Furthermore, experiments with diluted serum spiked with PON1 demonstrated recovery of PON1 activity near 100%.